Ceritinib is a novel triple negative breast cancer therapeutic agent.

BACKGROUND: Triple-negative breast cancers (TNBCs) are clinically aggressive subtypes of breast cancer. TNBC is difficult to treat with targeted agents due to the lack of commonly targeted therapies within this subtype. Androgen receptor (AR) has been detected in 12-55% of TNBCs. AR stimulates breast tumor growth in the absence of estrogen receptor (ER), and it has become an emerging molecular target in TNBC treatment. METHODS: Ceritinib is a small molecule inhibitor of tyrosine kinase and it is used in the therapy of non-small lung cancer patients. Enzalutamide is a small molecule compound targeting the androgen receptor and it is used to treat prostate cancer. Combination therapy of these drugs were investigated using AR positive breast cancer mouse xenograft models. Also, combination treatment of ceritinib and paclitaxel investigated using AR- and AR low mouse xenograft and patient derived xenograft models. RESULTS: We screened 133 FDA approved drugs that have a therapeutic effect of AR+ TNBC cells. From the screen, we identified two drugs, ceritinib and crizotinib. Since ceritinib has a well- defined role in androgen independent AR signaling pathways, we further investigated the effect of ceritinib. Ceritinib treatment inhibited RTK/ACK/AR pathway and other downstream pathways in AR+ TNBC cells. The combination of ceritinib and enzalutamide showed a robust inhibitory effect on cell growth of AR+ TNBC cells in vitro and in vivo. Interestingly Ceritinib inhibits FAK-YB-1 signaling pathway that leads to paclitaxel resistance in all types of TNBC cells. The combination of paclitaxel and ceritinib showed drastic inhibition of tumor growth compared to a single drug alone. CONCLUSIONS: To improve the response of AR antagonist in AR positive TNBC, we designed a novel combinational strategy comprised of enzalutamide and ceritinib to treat AR+ TNBC tumors through the dual blockade of androgen-dependent and androgen-independent AR signaling pathways. Furthermore, we introduced a novel therapeutic combination of ceritinib and paclitaxel for AR negative or AR-low TNBCs and this combination inhibited tumor growth to a great extent. All agents used in our study are FDA-approved, and thus the proposed combination therapy will likely be useful in the clinic.

Nischarin Deletion Reduces Oxidative Metabolism and Overall ATP: A Study Using a Novel NISCHΔ5-6 Knockout Mouse Model.

Nischarin (Nisch) is a cytosolic scaffolding protein that harbors tumor-suppressor-like characteristics. Previous studies have shown that Nisch functions as a scaffolding protein and regulates multiple biological activities. In the current study, we prepared a complete Nisch knockout model, for the first time, by deletion of exons 5 and 6. This knockout model was confirmed by Qrt-PCR and Western blotting with products from mouse embryonic fibroblast (MEF) cells. Embryos and adult mice of knockouts are significantly smaller than their wild-type counterparts. Deletion of Nisch enhanced cell migration, as demonstrated by wound type and transwell migration assays. Since the animals were small in size, we investigated Nisch's effect on metabolism by conducting several assays using the Seahorse analyzer system. These data indicate that Nisch null cells have lower oxygen consumption rates, lower ATP production, and lower levels of proton leak. We examined the expression of 15 genes involved in lipid and fat metabolism, as well as cell growth, and noted a significant increase in expression for many genes in Nischarin null animals. In summary, our results show that Nischarin plays an important physiological role in metabolic homeostasis.

Microparticles in systemic sclerosis: Potential pro-inflammatory mediators and pulmonary hypertension biomarkers.

BACKGROUND AND OBJECTIVE: Endothelial microparticles (EMP) are submicron vesicles released from endothelial cells. We aimed to determine the utility of EMP as biomarkers of pulmonary arterial hypertension (PAH) in systemic sclerosis (SSc) patients and the pathogenic role of microparticles (MP) in vascular inflammation. METHODS: Levels of EMP (CD144+, CD31+, CD62E+ and CD143+) were compared between three groups (10 SSc patients with PAH, 10 SSc patients without pulmonary hypertension (no-PH) and 10 healthy age- and sex-matched controls). Human pulmonary artery endothelial cells (HPAEC) were exposed in vitro to MP obtained from SSc patients or healthy controls, and levels of cytokines and inflammatory adhesion molecules were compared. RESULTS: CD144+ EMP were significantly higher in the SSc-PAH group compared to either the SSc-no PH or healthy controls (diagnostic accuracy 80%, P = 0.02). Compared to controls, SSc patients had higher CD31+/CD62E+ ratios, indicating larger contributions of apoptosis to EMP release (P = 0.04). Patients with limited SSc had significantly higher levels of CD143+ EMP compared to those with diffuse subtype (P = 0.008). When HPAEC were exposed to MP from SSc patients, there was a significant increase in inflammatory cytokines and adhesion molecules. Interestingly, exposure to healthy control MP caused a reduction in inflammatory markers. CONCLUSION: EMP (particularly CD144+) are promising biomarkers of PAH in SSc but require further study. MP isolated from SSc patients induced an increase in endothelial cell inflammation and may be an important pathogenic factor in SSc.

Treatment with intranasal iloprost reduces disease manifestations in a murine model of previously established COPD.

Pulmonary endothelial prostacyclin appears to be involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). The effect of treatment with a prostacyclin analog in animal models of previously established COPD is unknown. We evaluated the short- and long-term effect of iloprost on inflammation and airway hyperresponsiveness (AHR) in a murine model of COPD. Nineteen mice were exposed to LPS/elastase, followed by either three doses of intranasal iloprost or saline. In the long-term treatment experiment, 18 mice were exposed to LPS/elastase and then received 6 wk of iloprost or were left untreated as controls. In the short-term experiment, iloprost did not change AHR but significantly reduced serum IL-5 and IFN-γ. Long-term treatment with iloprost for both 2 and 6 wk significantly improved AHR. After 6 wk of iloprost, there was a reduction in bronchoalveolar lavage (BALF) neutrophils, serum IL-1ß (30.0 ± 9.2 vs. 64.8 ± 7.4 pg/ml, P = 0.045), IL-2 (36.5 ± 10.6 vs. 83.8 ± 0.4 pg/ml, P = 0.01), IL-10 (75.7 ± 9.3 vs. 96.5 ± 3.5 pg/ml, P = 0.02), and nitrite (15.1 ± 5.4 vs. 30.5 ± 10.7 µmol, P = 0.01). Smooth muscle actin (SMA) in the lung homogenate was also significantly reduced after iloprost treatment (P = 0.02), and SMA thickness was reduced in the small and medium blood vessels after iloprost (P < 0.001). In summary, short- and long-term treatment with intranasal iloprost significantly reduced systemic inflammation in an LPS/elastase COPD model. Long-term iloprost treatment also reduced AHR, serum nitrite, SMA, and BALF neutrophilia. These data encourage future investigations of prostanoid therapy as a novel treatment for COPD patients.

Role of Nischarin in the pathology of diseases: a special emphasis on breast cancer.

Nischarin has been demonstrated to have tumor suppressor functions. In this review, we comprehensively discuss up to date information about Nischarin. In addition, this paper aims to report the prognostic value, clinical relevance, and biological significance of the Nischarin gene (NISCH) in breast cancer (BCa) patients using the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and The Cancer Genome Atlas (TCGA) datasets. We evaluated NISCH gene expression and its correlation to patient survival, baseline expression, and expression variation based on age groups, tumor stage, tumor size, tumor grade, and lymph node status in different subtypes of BCa. Since NISCH has been extensively reported to inhibit EMT and cancer cell migration, we also checked for the correlation between NISCH and EMT genes in addition to the correlation between NISCH and cell migration genes. Our results indicate that NISCH is a tumor suppressor that plays a critical role in BCa initiation, progression, and tumor development. We find that there is a higher level of NISCH expression in normal breast tissues compared to breast cancer tissues. Also, aggressive subtypes of breast cancers, such as the triple negative/basal category, have decreased levels of NISCH as the disease progresses. Finally, we report that NISCH is inversely correlated with many EMT and cancer cell migration genes in BCa. Interestingly, we identified a significant negative correlation between NISCH expression and its methylation in breast cancer patients. Overall, the goal of this report is to establish a strong clinical basis for further investigation into the cellular, molecular, and physiological roles of NISCH in BCa. Ultimately, NISCH gene expression might be clinically harnessed as a biomarker or predictor of invasiveness and metastasis in BCa.

A combination of novel NSC small molecule inhibitor along with doxorubicin inhibits proliferation of triple-negative breast cancer through metabolic reprogramming.

Treatment of patients with triple-negative breast cancer (TNBC) has been challenging due to the absence of well-defined molecular targets and the highly invasive and proliferative nature of TNBC cells. Current treatments against TNBC have shown little promise due to high recurrence rate in patients. Consequently, there is a pressing need for novel and efficacious therapies against TNBC. Here, we report the discovery of a novel small molecule inhibitor (NSC33353) with potent anti-tumor activity against TNBC cells. The anti-proliferative effects of this small molecule inhibitor were determined using 2D and 3D cell proliferation assays. We found that NSC33353 significantly reduces the proliferation of TNBC cells in these assays. Using proteomics, next generation sequencing (NGS), and gene enrichment analysis, we investigated global regulatory pathways affected by this compound in TNBC cells. Proteomics data indicate a significant metabolic reprograming affecting both glycolytic enzymes and energy generation through oxidative phosphorylation. Subsequently, using metabolic (Seahorse) and enzymatic assays, we validated our proteomics and NGS analysis findings. Finally, we showed the inhibitory and anti-tumor effects of this small molecule in vitro and confirmed its inhibitory activity in vivo. Doxorubicin is one of the most effective agents in the treatment of TNBC and resistance to this drug has been a major problem. We show that the combination of NSC33353 and doxorubicin suppresses the growth of TNBC cells synergistically, suggesting that NSC33353 enhances TNBC sensitivity to doxorubicin. In summary, our data indicate that the small molecule inhibitor, NSC33353, exhibits anti-tumor activity in TNBC cells, and works in a synergistic fashion with a well-known chemotherapeutic agent.

Repurposing existing drugs for the treatment of COVID-19/SARS-CoV-2 infection: A review describing drug mechanisms of action.

The outbreak of a novel coronavirus (SARS-CoV-2) has caused a major public health concern across the globe. SARS-CoV-2 is the seventh coronavirus that is known to cause human disease. As of September 2020, SARS-CoV-2 has been reported in 213 countries and more than 31 million cases have been confirmed, with an estimated mortality rate of ∼3%. Unfortunately, a drug or vaccine is yet to be discovered to treat COVID-19. Thus, repurposing of existing cancer drugs will be a novel approach in treating COVID-19 patients. These drugs target viral replication cycle, viral entry and translocation to the nucleus. Some can enhance innate antiviral immune response as well. Hence this review focuses on comprehensive list of 22 drugs that work against COVID-19 infection. These drugs include fingolimod, colchicine, N4-hydroxycytidine, remdesivir, methylprednisone, oseltamivir, icatibant, perphanizine, viracept, emetine, homoharringtonine, aloxistatin, ribavirin, valrubicin, famotidine, almitrine, amprenavir, hesperidin, biorobin, cromolyn sodium, and antibodies- tocilzumab and sarilumab. Also, we provide a list of 31 drugs that are predicted to function against SARS-CoV-2 infection. In summary, we provide succinct overview of various therapeutic modalities. Among these 53 drugs, based on various clinical trials and literature, remdesivir, nelfinavir, methylpredinosolone, colchicine, famotidine and emetine may be used for COVID-19. SIGNIFICANCE: It is of utmost important priority to develop novel therapies for COVID-19. Since the effect of SARS-CoV-2 is so severe, slowing the spread of diseases will help the health care system, especially the number of visits to Intensive Care Unit (ICU) of any country. Several clinical trials are in works around the globe. Moreover, NCI developed a recent and robust response to COVID-19 pandemic. One of the NCI's goals is to screen cancer related drugs for identification of new therapies for COVID-19. https://www.cancer.gov/news-events/cancer-currents-blog/2020/covid-19-cancer-nci-response?cid=eb_govdel.

Global Sex Disparity of COVID-19: A Descriptive Review of Sex Hormones and Consideration for the Potential Therapeutic Use of Hormone Replacement Therapy in Older Adults.

The 2019-2020 SARS-related coronavirus-2 (SARS-CoV-2) pandemic has brought unprecedented challenges to healthcare sectors around the world. As of November 2020, there have been over 64 million confirmed cases and approaching 2 million deaths globally. Despite the large number of positive cases, there are very limited established standards of care and therapeutic options available. To date, there is still no Food and Drug Administration (FDA) approved vaccine for COVID-19, although there are several options in various clinical trial stages. Herein, we have performed a global review evaluating the roles of age and sex on COVID-19 hospitalizations, ICU admissions, deaths in hospitals, and deaths in nursing homes. We have identified a trend in which elderly and male patients are significantly affected by adverse outcomes. There is evidence suggesting that sex hormone levels can influence immune system function against SARS-CoV-2 infection, thus reducing the adverse effects of COVID-19. Since older adults have lower levels of these sex hormones, we therefore speculate, within rational scientific context, that sex steroids, such as estrogen and progesterone, needs further consideration for use as alternative therapeutic option for treating COVID-19 elderly patients. To our knowledge, this is the first comprehensive article evaluating the significance of sex hormones in COVID-19 outcomes in older adults.

Acute effect of inhaled iloprost on exercise dynamic hyperinflation in COPD patients: A randomized crossover study.

BACKGROUND AND OBJECTIVE: We tested whether the prostacyclin analog inhaled iloprost modulates dead space, dynamic hyperinflation (DH), and systemic inflammation/oxidative stress during maximal exercise in subjects with chronic obstructive pulmonary disease (COPD) who were not selected based on pulmonary hypertension (PH). METHODS: Twenty-four COPD patients with moderate-severe obstruction (age 59 ± 7 years, FEV1 53 ± 13% predicted) participated in a randomized, double-blind, placebo-controlled crossover trial. Each subject received a single nebulized dose of 5.0 µg iloprost or placebo on non-consecutive days followed by maximal cardiopulmonary exercise tests. The primary outcome was DH quantified by end-expiratory lung volume/total lung capacity ratio (EELV/TLC) at metabolic isotime. RESULTS: Inhaled iloprost was well-tolerated and reduced submaximal alveolar dead-space fraction but did not significantly reduce DH (0.70 ± 0.09 vs 0.69 ± 0.07 following placebo and iloprost, respectively, p = 0.38). Maximal exercise time (9.1 ± 2.3 vs 9.3 ± 2.2 min, p = 0.31) and peak oxygen uptake (17.4 ± 6.3 vs 17.9 ± 6.9 mL/kg/min, p = 0.30) were not significantly different following placebo versus iloprost. CONCLUSIONS: A single dose of inhaled iloprost was safe and reduced alveolar dead space fraction; however, it was not efficacious in modulating DH or improving exercise capacity in COPD patients who were not selected for the presence of PH.

Association of Serum Magnesium with Blood Pressure in Patients with Hypertensive Crises: A Retrospective Cross-Sectional Study.

The role of magnesium in blood pressure has been studied among hypertensive patients; however, there is a dearth of studies exploring the role of magnesium in hypertensive crises. The primary objective of this study was to evaluate the relationship between serum magnesium and blood pressure in patients with hypertensive crises. This was a single-center, retrospective, chart review, cross-sectional study of patients with hypertensive crises. Patients were included if they were eighteen years of age or older, with an international classification disease ninth revision (ICD-9) code of 401.9 (hypertensive crises: emergency or urgency) and a documented magnesium level on their electronic medical record. The primary outcome of the study was the correlation between serum magnesium and blood pressure (systolic blood pressure and diastolic blood pressure) in patients with hypertensive crises. Two hundred and ninety-three patients were included in the study. The primary outcome result showed that serum magnesium was positively correlated with systolic blood pressure (r = 0.143, p = 0.014), but not diastolic blood pressure. Conclusion: This study found a significant positive association between magnesium and systolic blood pressure, but not diastolic blood pressure, among patients with hypertensive crises. This positive association of serum magnesium with systolic blood pressure was maintained after adjusting for covariates. This study's findings suggest a potential role of magnesium in blood pressure among patients with hypertensive crises.

Evaluation of serum calcium differences in hypertensive crises and control patients: A randomly matched case-control study.

The role of calcium in blood pressure has been widely studied among hypertensive patients; however, no study has explored the role of calcium in hypertensive crises. The primary objective of this study is to evaluate the differences in serum calcium levels between hypertensive crises patients and a 1:1 random matched controls (age-, sex-, race-, diabetes, and body mass index matched). This study is a single-center, retrospective, chart review, case-control study of patients with hypertensive crises (case group) and patients without hypertensive crises (control group). Patients were included in the case group if they were 18 years of age or older with hypertensive crises and have a documented calcium level. The control group patients were required to be 18 years of age or older, have a documented calcium level, and have no diagnosis of hypertensive crises. The primary outcome of the study was to compare the mean serum calcium in patients with hypertensive crises vs patients without hypertensive crises. Five hundred and sixty-six patients were included in the study: 283 patients in both the case group and control group. The primary outcome results showed that serum calcium concentration was not significantly different between the case group (8.99 ± 0.78 mg/dL) and control group (8.96 ± 0.75 mg/dL) (P = .606). This study found no significant difference in serum calcium levels in patients with hypertensive crises compared to a random matched control group. Larger observational or experimental studies may be useful to evaluate the effect of calcium on blood pressure in hypertensive crises.

Evaluation of serum magnesium differences in hypertensive crises and control patients: A randomly matched case-control study.

Although the role of magnesium in blood pressure has been well studied among hypertensive patients, no study has explored the role of magnesium in hypertensive crises. The primary objective of this study is to evaluate the differences in serum magnesium levels between hypertensive crises patients and matched controls (age-, sex-, race-, and diabetes-matched) in a 1:1 random match. This study is a single-center, retrospective, chart review, case-control study of patients with hypertensive crises (case group) and patients without hypertensive crises (control group). Patients were included in the case group if they were 18 years of age or older with hypertensive crises and have a documented magnesium level. The control group patients were required to be 18 years of age or older, have no diagnosis of hypertensive crises, and have a documented magnesium level. The primary outcome of the study was to compare the mean serum magnesium in patients with hypertensive crises versus patients without hypertensive crises. Three hundred and fifty-eight patients were included in the study: 179 patients in both the case group and control group. The primary outcome results showed that serum magnesium concentration was not significantly different between the case group (1.89 ± 0.29 mg/dl) and control group (1.90 ± 0.31 mg/dl) (p = .787). This study found no significant difference in serum magnesium levels in patients with hypertensive crises compared to a random matched control group. Larger observational or experimental studies may be useful to evaluate the effect of magnesium on blood pressure in hypertensive crises.

Bilateral Vascular Repair in a Patient with Multiple Upper Extremity Injury Presenting at a Teaching Hospital-Case Report and Literature Review.

Penetrating trauma to the upper extremity will usually result in vascular injuries, which mostly also involves nerves and tendons. Morbidity related to upper extremity vascular injuries usually occurs due to the associated injuries of the nerves, tendons, and bone. Early presentation to a trauma centre and prompt intervention will reduce morbidity associated with upper extremity vascular injuries.

Pioglitazone's beneficial effects on erectile function preservation after cavernosal nerve injury in the rat are negated by inhibition of the insulin-like growth factor-1 receptor: a preclinical study.

To determine if the insulin-like growth factor-1 (IGF-1) pathway is involved in the improvement in erectile function recovery in rats after nerve crush injury treated with pioglitazone (Pio). Sprague-Dawley rats were divided into four groups. The first group received sham operation (n = 5). The second group underwent bilateral cavernous nerve injury (BCNI, n = 7). The third group received BCNI and Pio treatment (BCNI + Pio, n = 7), whereas the fourth group underwent BCNI with Pio treatment and IGF-1 inhibition (BCNI + Pio + JB-1, n = 7). The IGF-1 receptor (IGF-1R) was inhibited by JB-1, a small molecular antagonist of the receptor. After 14 days of treatment, erectile function was measured via intracorporal pressure normalized to mean arterial pressure (ICP/MAP) and the major pelvic ganglion and cavernous nerve harvested for western blot and immunohistochemistry (IHC) of phosphorylated-IGF-1Rß (p-IGF-1Rß), phosphorylated-ERK1/2 (p-ERK1/2), and neuronal NOS (nNOS). BCNI + Pio animals exhibited improvements in ICP/MAP, similar to Sham animals, and BCNI + Pio + JB-1 rats demonstrated a reduced ICP/MAP similar to BCNI-only rats at all measured voltages. Western blot results showed upregulation of p-IGF-1Rß was observed in the BCNI + Pio group. Low levels of p-ERK1/2 were seen in the JB-1-treated animals. The immunoblot results were supported by IHC findings. Intense IHC staining of nNOS was detected in the BCNI + Pio group. The group treated with JB-1 showed minimal protein expression of p-ERK1/2, nNOS, and p-IGF-1Rß. Pio improves erectile function in rats undergoing BCNI via an IGF-1-mediated pathway.

Clinical Effects of Cigarette Smoking: Epidemiologic Impact and Review of Pharmacotherapy Options.

Cigarette smoking-a crucial modifiable risk factor for organ system diseases and cancer-remains prevalent in the United States and globally. In this literature review, we aim to summarize the epidemiology of cigarette smoking and tobacco use in the United States, pharmacology of nicotine-the active constituent of tobacco, and health consequence of cigarette smoking. This article also reviews behavioral and pharmacologic interventions for cigarette smokers and provides cost estimates for approved pharmacologic interventions in the United States. A literature search was conducted on Google Scholar, EBSCOhost, ClinicalKey, and PubMed databases using the following headings in combination or separately: cigarette smoking, tobacco smoking, epidemiology in the United States, health consequences of cigarette smoking, pharmacologic therapy for cigarette smoking, and non-pharmacologic therapy for cigarette smoking. This review found that efficacious non-pharmacologic interventions and pharmacologic therapy are available for cessation of cigarette smoking. Given the availability of efficacious interventions for cigarette smoking cessation, concerted efforts should be made by healthcare providers and public health professionals to promote smoking cessation as a valuable approach for reducing non-smokers' exposure to environmental tobacco smoke.