Insights into the therapeutic outcomes of trimetazidine/doxorubicin combination in Ehrlich solid-phase carcinoma mouse tumor model.

One of the key features of cancer is metabolic reprogramming that can be exploited to sensitize cancer cells to chemotherapy. Trimetazidine (TMZ) is a metabolic anti-ischemic drug that blocks the activity of long-chain 3-ketoacyl CoA thiolase leading to the inhibition of fatty acid oxidation. AIMS: The objective of the current investigation was to evaluate the idea that TMZ could synergize the antitumor activity of doxorubicin (DOX). MAIN METHODS: The hypothesis was examined in vitro using the human breast cancer cell lines MCF-7 and MDA-MB231. In addition, the in vivo experiments were conducted using the Ehrlich solid phase carcinoma model. KEY FINDINGS: In vitro cytotoxicity experiments demonstrated that TMZ improved the potency of DOX in MCF-7 cell lines in a synergistic manner. In vivo testing confirmed that DOX/TMZ combination exhibits synergistic effect at both DOX/TMZ 1:10 and 1:5 ratios, where DOX was administered at one tenth and one fifth of its original dose, respectively. The co-treatment (1:5 ratio) significantly reduced tumor Nicotinamide adenine dinucleotide (NAD)+/NADH ratio (6.1-fold) and Adenosine triphosphate (ATP) levels (61 %) with concurrent activation of AMP-activated protein kinase (AMPK) (2.2-fold) and peroxisome proliferator-activated receptor-gamma coactivator (PGC)1-α (5.5-fold) protein expression versus control. The same treatment decreased the nuclear levels of NF-κB (p65) (57.5 %) and induced tumor apoptosis as evidenced by elevated Bax/Bcl-2 ratio (6.8-fold) along with active caspase-3 levels (6.6-fold) against control. SIGNIFICANCE: The current investigation constitutes a proof-of-concept study that provided preclinical evidence for the anticancer activity of DOX/TMZ combination and warrants further investigation for repurposing TMZ in DOX protocols.

The natural isoflavone Biochanin-A synergizes 5-fluorouracil anticancer activity in vitro and in vivo in Ehrlich solid-phase carcinoma model.

Isoflavones are considered one of the most extensively studied plant-derived phytoestrogenic compounds. Of these, Biochanin A (Bio-A), a natural isoflavone abundant in cabbage, alfalfa, and red clover, has drawn a lot of attention. As reported in multiple studies, Bio-A possesses a promising anticancer activity against estrogen receptor-positive (ER+) breast cancer. The current study investigated the working hypothesis that Bio-A could synergistically enhance the potency of 5-fluorouracil (5-FU) in ER+ breast cancer. The hypothesis was tested both in vitro on hormone receptor-positive (MCF-7) and triple-negative breast cancer cells (MDA-MB231). Additionally, in vivo studies were performed in the Ehrlich solid-phase carcinoma mouse model. The in vitro cytotoxicity studies revealed that Bio-A synergistically increased the potency of 5-FU in both MCF-7 and MDA-MB231 cell lines. The synergistic effect of 5-FU/Bio-A combination was verified in vivo. The combination therapy (where 5-FU was used at one fourth its full dose) led to a significant 75% reduction in tumor volume after two treatment cycles. This was in addition to producing a significant 2.1-fold increase in tumor necrosis area% compared to mock-treated control. In conclusion, the current study presents the first preclinical evidence for the potential merit of 5-FU/Bio-A combination for the treatment of ER+ breast cancer. The synergistic antitumor effect of Bio-A/ 5-FU combination can be, at least partly, attributed to Bio-A-mediated suppression of ER-α/Akt axis and the augmentation of 5-FU-mediated proapoptotic effects. © 2022 John Wiley & Sons, Ltd.

Insights into the therapeutic potential of histone deacetylase inhibitor/immunotherapy combination regimens in solid tumors.

Solid tumors including skin, lung, breast, colon, and prostate cancers comprise the most diagnosed cancers worldwide. Treatment of such cancers is still challenging specially in the advanced/metastatic setting. The growing understanding of the tumor microenvironment has revolutionized the cancer therapy paradigms. Targeting programmed death-1 (PD-1)/PD-L1 immune checkpoint has been extensively studied over this decade as a new trend in the management of hard-to-treat cancers by harnessing the power of the immune system to eradicate the tumors. Yet, low response rate and resistance were observed when immunotherapies were tested as monotherapy. This urged the need to develop combinatorial regimens of immunotherapy with other immune modulatory agents to enhance its therapeutic potential and help in reverting the resistance. Epigenetic modifiers such as histone deacetylase inhibitors (HDACIs) showed favorable effects on modulating the tumor microenvironment along with the host immune cells. This qualified HDACIs as an attractive candidate class to be tested in combination with immunotherapy. In this review we cover the ongoing clinical trials that investigate the safety and/or the efficacy of HDACI/immunotherapy combinations in solid tumors including skin cancer, prostate cancer, breast cancer, colorectal cancer, lung cancer and recapitulates areas for future research.

Implications of WHO COVID-19 interim guideline 2020.5 on the comprehensive care for infected persons in Africa Before, during and after clinical management of cases.

The novel coronavirus disease 2019 (COVID-19) is one of the biggest public health crises globally. Although Africa did not display the worst-case scenario compared to other continents, fears were still at its peak since Africa was already suffering from a heavy load of other life-threatening infectious diseases such as HIV/AIDS and malaria. Other factors that were anticipated to complicate Africa's outcomes include the lack of resources for diagnosis and contact tracing along with the low capacity of specialized management facilities per capita. The current review aims at assessing and generating discussions on the realities, and pros and cons of the WHO COVID-19 interim guidance 2020.5 considering the known peculiarities of the African continent. A comprehensive evaluation was done for COVID-19-related data published across PubMed and Google Scholar (date of the last search: August 17, 2020) with emphasis on clinical management and psychosocial aspects. Predefined filters were then applied in data screening as detailed in the methods. Specifically, we interrogated the WHO 2020.5 guideline viz-a-viz health priority and health financing in Africa, COVID-19 case contact tracing and risk assessment, clinical management of COVID-19 cases as well as strategies for tackling stigmatization and psychosocial challenges encountered by COVID-19 survivors. The outcomes of this work provide links between these vital sub-themes which may impact the containment and management of COVID-19 cases in Africa in the long-term. The chief recommendation of the current study is the necessity of prudent filtration of the global findings along with regional modelling of the global care guidelines for acting properly in response to this health threat on the regional level without exposing our populations to further unnecessary adversities.

The potential neuroprotective effect of diosmin in rotenone-induced model of Parkinson's disease in rats.

Most treatments for Parkinson's disease (PD) focus on improving the symptoms and the dopaminergic effects; nevertheless, they cannot delay the disease progression. Diosmin (DM), a naturally occurring flavone that is obtained from citrus fruits, has demonstrated anti-apoptotic, anti-inflammatory and antioxidative properties in many diseases. This study aimed to assess the neuroprotective effects of diosmin in rotenone-induced rat model of PD and investigate its potential underlying mechanisms. A preliminary dose-response study was conducted where rats were treated with DM (50,100 and 200 mg/kg, p.o.) concomitantly with rotenone (2 mg/kg, s.c.) for 4 weeks. Catalepsy, motor impairment, spontaneous locomotion, body weight, histological examination and tyrosine hydroxylase (TH) immunoreactivity were evaluated in both the midbrains and striata of rats. Treatment with DM (200 mg/kg) showed the most promising outcome therefore, it was selected for further evaluation of α-synuclein, Bax, Bcl2, nuclear factor kappa B (NF-кB), nuclear factor erythroid 2- related factor 2 (Nrf2), and heme oxygenase-1 (HO-1), in addition to biochemical analysis of tumor necrosis factor-α (TNF-α). Results showed that DM (200 mg/kg, p.o.) prevented rotenone-induced motor impairment, weight reduction and histological damage. Furthermore, it significantly inhibited rotenone-induced decrease in TH expression. These results were correlated with reduction in α-synuclein immunoreactivity, together with improvement of Bax/Bcl2 ratio compared to rotenone group. DM also attenuated rotenone-induced increase in NF-кB expression as well as TNF- α levels. Moreover, DM inhibited rotenone-induced upregulation of Nrf2/HO-1 pathway. Thus, the current study suggests that DM might be a promising candidate for managing the neuropathological course of PD.

SARS-CoV-2 Viral Shedding and Transmission Dynamics: Implications of WHO COVID-19 Discharge Guidelines.

The evolving nature of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has necessitated periodic revisions of COVID-19 patient treatment and discharge guidelines. Since the identification of the first COVID-19 cases in November 2019, the World Health Organization (WHO) has played a crucial role in tackling the country-level pandemic preparedness and patient management protocols. Among others, the WHO provided a guideline on the clinical management of COVID-19 patients according to which patients can be released from isolation centers on the 10th day following clinical symptom manifestation, with a minimum of 72 additional hours following the resolution of symptoms. However, emerging direct evidence indicating the possibility of viral shedding 14 days after the onset of symptoms called for evaluation of the current WHO discharge recommendations. In this review article, we carried out comprehensive literature analysis of viral shedding with specific focus on the duration of viral shedding and infectivity in asymptomatic and symptomatic (mild, moderate, and severe forms) COVID-19 patients. Our literature search indicates that even though, there are specific instances where the current protocols may not be applicable ( such as in immune-compromised patients there is no strong evidence to contradict the current WHO discharge criteria.

Rosuvastatin and low-dose carvedilol combination protects against isoprenaline-induced myocardial infarction in rats: Role of PI3K/Akt/Nrf2/HO-1 signalling.

Rosuvastatin has been shown to activate PI3K/Akt/Nrf2/HO-1 pathway, which promotes cell survival in the myocardium. This study investigated the therapeutic benefit of adding rosuvastatin to low-dose carvedilol in protection against myocardial infarction (MI). Rosuvastatin (RSV) and carvedilol (CAR) were given for 7 consecutive days with concurrent administration of two doses of isoprenaline (ISP) on 6th and 7th days to induce MI. Isoprenaline injections caused detrimental alterations in the myocardial architecture and electrocardiogram (ECG) pattern and significantly increased the infarct size, heart index and serum levels of cardiotoxicity markers compared to the control group. ISP induced oxidative damage, inflammatory and apoptotic events and downregulated PI3K/Akt/Nrf2/HO-1 signalling pathway compared to the control values. Treatment with low-dose CAR and/or RSV prevented the ECG and histopathological alterations induced by ISP, and also reduced the infarct size, heart index, serum creatine kinase-MB, cardiac troponin-I and C-reactive protein levels compared to ISP group. CAR and/or RSV treatment restored the activity of superoxide dismutase and total antioxidant capacity with a consequent reduction in lipid peroxides level. Further, they decreased the expression of nuclear factor (NF)-κB (p65) and increased the phosphorylated PI3K and Akt, which may activate the anti-apoptotic signalling as evidenced by the decreased active caspase 3 level. The combination therapy has a more significant effect in the most studied parameters than their monotherapy, which may be because of the activation of PI3K/Akt Nrf2/HO-1 pro-survival signalling pathway. This study highlights the potential benefits of combining RSV with low-dose CAR in case of MI.

Nuclear factor-κB signaling inhibitors revert multidrug-resistance in breast cancer cells.

The emergence of multidrug resistance (MDR) is among the crucial obstacles to breast cancer therapy success. The transcription factor nuclear factor (NF)-κB is correlated to the pathogenesis of breast cancer and resistance to therapy. NF-κB augments the expression of MDR1 gene, which encodes for the membrane transporter P-glycoprotein (P-gp) in cancer cells. Since NF-κB activity is considered to be relatively high in particular when it comes to breast cancer, in the present work, we proposed that the inhibition of NF-κB activity can augment and enhance the sensitivity of breast cancer cells to chemotherapy such as doxorubicin (DOX) by virtue of MDR modulation. Our results demonstrated that the DOX-resistant MCF-7 and MDA-MB-231 clones exhibit higher NF-κB (p65) activity, which is linked to the upregulated expression of ABCB1 and ABCC1 transporter proteins. Combined treatment with NF-kB inhibitors (pentoxifylline and bortezomib) sensitized the resistant breast cancer cells to DOX. Such synergy was compromised by forced overexpression of p65. The DOX/NF-κB inhibitor combinations hampered NF-κB (p65) activation and downregulated MDR efflux transporters' level. Breast cancer cell migration was sharply suppressed in cells co-treated with DOX/NF-κB inhibitors. The same treatments successfully enhanced DOX-mediated induction of apoptosis, which is reflected by the elevated ratio of annexin-V/PI positively stained cells, along with the activation of other apoptotic markers. In conclusion, the data generated from this study provide insights for future translational investigations introducing the use of the clinically approved NF-κB inhibitors as an adjuvant in the treatment protocols of resistant breast cancer to overcome the multidrug resistance and enhance the therapeutic outcomes.

Caffeic acid phenethyl ester counteracts doxorubicin-induced chemobrain in Sprague-Dawley rats: Emphasis on the modulation of oxidative stress and neuroinflammation.

Chemotherapy-induced cognitive dysfunction (chemobrain) is one of the major complaints for cancer patients treated with chemotherapy such as Doxorubicin (DOX). The induction of oxidative stress and neuroinflammation were identified as major contributors to such adverse effect. Caffeic acid phenethyl ester (CAPE) is a natural polyphenolic compound, that exhibits unique context-dependent antioxidant activity. It exhibits pro-oxidant effects in cancer cells, while it is a potent antioxidant and cytoprotective in normal cells. The present study was designed to investigate the potential neuroprotective effects of CAPE against DOX-induced cognitive impairment. Chemobrain was induced in Sprague Dawley rats via systemic DOX administration once per week for 4 weeks (2 mg/kg/week, i.p.). CAPE was administered at 10 or 20 µmol/kg/day, i.p., 5 days per week for 4 weeks. Morris water maze (MWM) and passive avoidance tests were used to assess learning and memory functions. Oxidative stress was evaluated via the colorimetric determination of GSH and MDA levels in both hippocampal and prefrontal cortex brain regions. However, inflammatory markers, acetylcholine levels, and neuronal cell apoptosis were assessed in the same brain areas using immunoassays including either ELISA, western blotting or immunohistochemistry. DOX produced significant impairment in learning and memory as indicated by the data generated from MWM and step-through passive avoidance tests. Additionally DOX-triggered oxidative stress as evidenced from the reduction in GSH levels and increased lipid peroxidation. Treatment with DOX resulted in neuroinflammation as indicated by the increase in NF-kB (p65) nuclear translocation in addition to boosting the levels of pro-inflammatory mediators (COX-II/TNF-α) along with the increased levels of glial fibrillary acid protein (GFAP) in the tested tissues. Moreover, DOX reduced acetylcholine levels and augmented neuronal cell apoptosis as supported by the increased active caspase-3 levels. Co-treatment with CAPE significantly counteracted DOX-induced behavioral and molecular abnormalities in rat brain tissues. Our results provide the first preclinical evidence for CAPE promising neuroprotective activity against DOX-induced neurodegeneration and memory deficits.

Revolutionizing the landscape of colorectal cancer treatment: The potential role of immune checkpoint inhibitors.

Colorectal cancer (CRC) represents the third cause of cancer-related mortalities worldwide. The progression of CRC to the metastatic phase significantly compromises the overall survival rates. Despite the advances in the therapeutic protocols, CRC treatment is still challenging. Cancer immunotherapy joined the ranks of surgery, chemotherapy, radiotherapy and targeted therapy as the fifth pillar in the foundation of cancer therapeutics. Interruption of the immunosuppressive signals within the tumor microenvironment and reactivation of antitumor immunity via targeting the molecular immune checkpoints generated promising therapeutic outcomes in several types of hard-to-treat cancers. The year 2017 witnessed the first US Food and Drug Administration (FDA) approval of immune checkpoint inhibitor (ICI) immunotherapy for the management of CRC. The approval was granted to pembrolizumab (anti-PD-1) for the treatment of patients with advanced/metastatic solid malignancies with mismatch-repair deficiency including CRCs. Such natively immunogenic tumors constitute only a minor percentage of all CRCs. Therefore, it is imperative to utilize novel combinatorial regimens to enhance the response of a wider range of CRC tumors to cancer immunotherapy and help in extending the survival rates in patients with advanced/metastatic disease. This review highlights the novel approaches under clinical development to overcome the resistance of CRCs to immunotherapy and improve the therapeutic outcomes.

The natural flavonoid galangin ameliorates dextran sulphate sodium-induced ulcerative colitis in mice: Effect on Toll-like receptor 4, inflammation and oxidative stress.

This study was carried out to investigate the potential therapeutic effect of galangin, a promising active principle of honeybee propolis, in dextran sulphate sodium (DSS)-induced colitis in mice. We explored the possible underlying mechanisms for galangin action and the therapeutic benefit of adding galangin to the standard therapy sulphasalazine. A galangin dose of 40 mg/kg was selected based on a preliminary dose-selection study for investigation in a 4-week cyclical model of DSS-induced colitis. Mice received 3% DSS in their drinking water during the first and third weeks and were administered the treatments (40 mg/kg galangin, 100 mg/kg sulphasalazine and a combination of 20 mg/kg galangin and 50 mg/kg sulphasalazine) daily starting from the second week. Galangin significantly ameliorated DSS-induced histopathological alterations and tissue injury, down-regulated Toll-like receptor 4 expression, suppressed NF-κB p65 activation, lowered inflammatory cytokine levels and demonstrated antioxidant effects. The combination of galangin and sulphasalazine at half doses yielded comparable results to either drug alone at full dose. This study highlights galangin as a promising therapy for colitis management.

Immunomodulatory MicroRNAs in cancer: targeting immune checkpoints and the tumor microenvironment.

Cancer immunotherapy represents a promising new era in cancer management due to the relatively high safety margins and selectivity, compared to the classical cancer chemotherapeutic agents. However, there is an imperative need to overcome tumor resistance in order to improve clinical outcomes and maximize the benefits of cancer immunotherapy. The interaction between the programmed cell death-1 (PD-1) receptor and its ligand PD-L1 is a vital immune checkpoint that is often adopted by cancer cells to undergo immune evasion. PD-1/PD-L1 signaling is regulated at multiple levels through the crosstalk with other immune targets or relevant signaling partners involved in the cancer progression. Among the significant epigenetic players that are implicated in modulating the immune system are microRNAs (miRNAs). A complex system of these noncoding RNAs regulates the gene expression at the post-transcriptional level and plays a significant role in the modulation of both innate and the adaptive immune systems. The expression profile of immune-modulatory miRNAs might be useful as a predictive biomarker for the response and clinical outcomes in cancer immunotherapy. Therefore, in the current review, we highlighted the role of miRNAs in cancer immune evasion through a critical discussion of their impact on key immune checkpoints as well as the role of miRNAs in cancer progression and resistance.

Tackling molecular targets beyond PD-1/PD-L1: Novel approaches to boost patients' response to cancer immunotherapy.

In the new era of immunotherapy, which has changed the clinical oncology practice guidelines, there is a pressing need for finding novel approaches to tune up the clinical outcomes of immunotherapy and extend its benefits to a wider cohort of cancer patients. Several non-classical molecular immune targets beyond PD-1/PD-L1 signaling were shown to be engaged as feedback resistance circuits to shut down the antitumor immune response mediated by the classical immune checkpoint inhibitors. Those include T-cell inducible co-stimulator (ICOS), CD40, CD47, V-domain Ig suppressor of T-cell activation (VISTA), cyclin-dependent kinase (CDK)12, enhancer of Zeste homolog 2 (EZH2), toll-like receptors (TLRs) and OX-40 (CD134). Herein we critically discussed the latest studies concerned with understanding the mechanisms involved in the negative clinical response to classical immunotherapies and strategies to optimize the efficacy of cancer immunotherapy through novel combinatorial approaches.

The impact of Catechol-O-methyl transferase knockdown on the cell proliferation of hormone-responsive cancers.

Estrogen (E2) plays a central role in the development and progression of hormone-responsive cancers. Estrogen metabolites exhibit either stimulatory or inhibitory roles on breast and prostate cells. The catechol metabolite 4-hydroxyestradiol (4-OHE2) enhances cell proliferation, while 2-methoxyestradiol (2 ME) possesses anticancer activity. The major metabolizing enzyme responsible for detoxifying the deleterious metabolite 4-OHE2 and forming the anticancer metabolite 2 ME is Catechol-O-Methyl Transferase (COMT). The current work investigated the relationship between the expression level of COMT and the cell proliferation of hormone-responsive cancers. The results showed that COMT silencing enhanced the cell proliferation of ER-α positive cancer cells MCF-7 and PC-3 but not the cells that lack ER-α expression as MDA-MB231 and DU-145. The data generated from our study provides a better understanding of the effect of COMT on critical signaling pathways involved in the development and progression of breast cancer (BC) and prostate cancer (PC) including ER-α, p21cip1, p27kip1, NF-κB (P65) and CYP19A1. These findings suggest that COMT enzyme plays a tumor suppressor role in hormone receptor-positive tumors which opens the door for future studies to validate COMT expression as a novel biomarker for the prediction of cancer aggressiveness and treatment efficacy.

Design, synthesis, biological evaluation and dynamics simulation of indazole derivatives with antiangiogenic and antiproliferative anticancer activity.

VEGFR-2 has a pivotal role in promoting cancer angiogenesis. Herein, two series of novel indazole-based derivatives were designed, synthesized and evaluated for their in vitro inhibitory action against VEGFR-2 kinase enzyme. The second series 11a-e exhibited better potency than the first one 7a-d and 8a-f. Compounds 11b, 11c and 11e exhibited the most potent action, with IC50 of 5.4 nM, 5.6 nM and 7 nM, respectively. As a measure of cellular VEGFR-2 inhibition, compounds 11b and 11c showed strong inhibition of human umbilical vein endothelial cells (HUVEC) proliferation with 80% and 99.6% inhibition at 10 µM concentration, respectively. Attempting to interpret SAR of the synthesized compounds, and provide a basis for further optimization; a comprehensive modeling study was implemented. Molecular docking, dynamics simulation and free energy calculation of the synthesized compounds along with known VEGFR-2 inhibitors were applied. The study illustrated the effect of several factors on VEGFR-2 inhibition, such as the interaction with solvent accessible region of the enzyme, the presence of NH linker and the degree of conformational restriction. Finally, our compounds were evaluated for their in vitro anti-proliferative effect against the full NCI panel of cancer cell lines, where compounds 11a and 11c displayed mean GI% of 93 and 130%, respectively, and showed partly a better behavior than the FDA approved drug sorafenib, with respect to activity (GI50) and safety (LC50) against several cell lines. Thus, compound 11c represents a promising candidate for cancer treatment through antiangiogenic dependent and antiangiogenic independent modes of action.

Caffeic acid phenethyl ester guards against benign prostate hypertrophy in rats: Role of IGF-1R/protein kinase-B (Akt)/ß-catenin signaling.

Benign prostate hypertrophy (BPH) is among the most common diseases with a huge impact on the quality of life of elderly men. There is a current need for the development of well-tolerated and effective preventive strategies to improve the clinical outcome. Caffeic acid phenethyl ester (CAPE) is an important active ingredient isolated from honey-bee propolis with potent anti-proliferative, anti-inflammatory and antioxidant effects. These properties promote CAPE as a promising candidate to be tested as an alternative therapy for BPH, which is still uninvestigated. Herein, we tested the ability of CAPE to guard against testosterone-induced BPH and investigated the involvement of IGF1-R/Akt/ß-catenin signaling as a protective mechanism in testosterone-induced BPH rat model. Treatment with CAPE reduced testosterone-induced increase in the prostate index and histopathological alterations. In addition, co-treatment with CAPE significantly suppressed insulin-like growth factor-1 receptor (IGF-1R)/Akt/ß-catenin/cyclinD1 axis as well as tumor necrosis factor-α level and nuclear factor (NF)-kB activity. Furthermore, the treatment with CAPE replenished the antioxidant defense systems, superoxide dismutase (SOD) and reduced glutathione (GSH) with subsequent reduction in prostate tissue lipid peroxides. This study highlights the potential merit of CAPE-enriched propolis formulations to protect elderly men against the development of BPH. © 2018 IUBMB Life, 70(6):519-528, 2018.

Immunotherapy, an evolving approach for the management of triple negative breast cancer: Converting non-responders to responders.

Immunotherapy comprises a promising new era in cancer therapy. Immune checkpoint inhibitors targeting either the programmed death (PD)-1 receptor or its ligand PD-L1 were first approved by the Food and Drug Administration (FDA) for the management of metastatic melanoma in 2011. The approval of this class is being extended to include other types of immunogenic tumors. Although breast cancer (BC) was first categorized as non-immunogenic tumor type, there are certain subsets of BC that showed a high level of tumor infiltrating lymphocytes (TILs). Those subsets include the triple negative breast cancer (TNBC) and HER-2 positive breast tumors. Preliminary data from clinical trials presented promising outcomes for patients with advanced stage/metastatic TNBC. While the objective response rate (ORR) was relatively low, it is still promising because of the observation that the patients who respond to the treatment with immune checkpoint blockade have favorable prognosis and often show a significant increase in the overall survival. Therefore, the main challenge is to find ways to enhance the tumor response to such therapy and to convert the non-responders to responders. This will consequently bring new hopes for patients with advanced stage metastatic TNBC and help to decrease death tolls from this devastating disease. In the current review, we are highlighting and discussing the up-to-date strategies adopted at either the preclinical or the clinical settings to enhance tumor responsiveness to immunotherapy.

Caffeic acid phenethyl ester protects against glucocorticoid-induced osteoporosis in vivo: Impact on oxidative stress and RANKL/OPG signals.

Glucocorticoid-induced osteoporosis (GIO) is one of the most common causes of secondary osteoporosis. Given that glucocorticoids are considered as a main component of the treatment protocols for a variety of inflammation and immune-mediated diseases besides its use as adjuvant to several chemotherapeutic agents, it is crucial to find ways to overcome this critical adverse effect. Caffeic acid phenethyl ester (CAPE), which is a natural compound derived from honeybee propolis displayed promising antiosteoporotic effects against mechanical bone injury in various studies. The current work aimed at investigating the potential protective effect of CAPE against GIO in vivo with emphasis on the modulation of oxidative status and receptor activator of NF-kB ligand (RANKL)/osteoprotegrin (OPG) signaling. The results showed that CAPE opposed dexamethasone (DEX)-mediated alterations in bone histology and tartarate-resistant acid phosphatase (TRAP) activity. In addition, CAPE restored oxidative balance, Runt-related transcription factor 2 (RunX2) expression and reduced caspase-3 activity in femur tissues. Co-administration of CAPE with DEX normalized RANKL/OPG ratio and Akt activation indicating a reduction in DEX-osteoclastogenesis. In conclusion, concurrent treatment of CAPE with DEX exhibited promising effects in the protection against DEX-induced osteoporosis through opposing osteoclastogenesis and protecting osteoblasts. The potent antioxidant activity of CAPE is, at least in part, involved in its anti-apoptotic effects and modulation of RunX2 and RANKL/OPG signals. The use of CAPE-enriched propolis formulas is strongly recommended for patients on chronic glucocorticoid therapy to help in the attenuation of GIO.