A Comprehensive Review of the Use of Antioxidants and Natural Products in Cancer Patients Receiving Anticancer Therapy.

Cancer is the leading cause of mortality and morbidity worldwide. The side effects of cancer treatment affect the quality of life. Cancer patients search for antioxidant dietary supplements and natural products during or after conventional cancer treatment for the alleviation of side effects, improvement of the benefits of treatment, and promotion of well-being. However, the efficacy and safety of these products remain controversial; moreover, previous data do not support the standardized use of those alternative treatments in clinics. The current study reviewed the manuscripts reporting the administration of antioxidants and natural products during cancer treatment and revised preclinical and clinical studies on various types of cancer. Most of the positive results were obtained from experimental animal models; however, human clinical studies are discouraging in this regard. Therefore, further precise and distinguishable studies are required regarding antioxidant dietary supplementation. Future studies are also needed to clarify dietary supplements' mechanism of action and pharmacokinetics in a suitable cancer patient population that will benefit the therapeutic regimens. Despite the popularity of dietary supplements, clinicians and patients should always consider their potential benefits and risks. Patients should discuss with their physician before taking any dietary antioxidant supplements or natural products.

The Effects of Martial Arts on Cancer-Related Fatigue and Quality of Life in Cancer Patients: An Up-to-Date Systematic Review and Meta-Analysis of Randomized Controlled Clinical Trials.

BACKGROUND: To evaluate and synthesize the existing evidence of the effects of practicing martial arts by cancer patients and cancer survivors in relation to overall quality of life (QoL) and cancer-related fatigue (CRF). METHODS: Randomized controlled trials (RCTs) from 1 January 2000 to 5 November 2020 investigating the impact of martial arts were compared with any control intervention for overall QoL and CRF among cancer patients and survivors. Publication quality and risk of bias were assessed using the Cochrane handbook of systematic reviews. RESULTS: According to the electronic search, 17 RCTs were retrieved including 1103 cancer patients. Martial arts significantly improved social function, compared to that in the control group (SMD = -0.88, 95% CI: -1.36, -0.39; p = 0.0004). Moreover, martial arts significantly improved functioning, compared to the control group (SMD = 0.68, 95% CI: 0.39-0.96; p < 0.00001). Martial arts significantly reduced CRF, compared to that in the control group (SMD = -0.51, 95% CI: -0.80, -0.22; p = 0.0005, I2 > 95%). CONCLUSIONS: The results of our systematic review and meta-analysis reveal that the effects of practicing martial arts on CRF and QoL in cancer patients and survivors are inconclusive. Some potential effects were seen for social function and CRF, although the results were inconsistent across different measurement methods. There is a need for larger and more homogeneous clinical trials encompassing different cancer types and specific martial arts disciplines to make more extensive and definitive cancer- and symptom-specific recommendations.

Computational screening of dual inhibitors from FDA approved antiviral drugs on SARS-CoV-2 spike protein and the main protease using molecular docking approach.

The deadly disease-causing novel coronavirus has recently swept across the world and endangered many human lives. Although, various research on therapeutic measures to solve this pandemic crisis has been published; no favourable results have been achieved. We propose the use of potential FDA-approved dual inhibitors which can inhibit two targets (either on entry-level or the main protease) for the effective treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We screened 12 FDA-approved antiviral inhibitors listed in Drug bank and analysed the ADMET properties of each drug of interest to study the bioavailability, safety and toxicity. Two potential targets, the spike protein and the main protease of SARS-CoV-2 obtained from PDB have been used for molecular docking. All the selected drugs were docked with both targets and demonstrated strong hydrogen bond (HB) interactions in multiple active sites. Amongst these, the range of binding energy was from 3-7 kcal/mol for spike protein and 2-8 kcal/mol for the main protease. Upon comparison of all the processed drugs ganciclovir and zanamivir displayed significant binding energy with HB interactions with both, spike (-9.2 and -9 kcal/mol respectively) and the main protease (-9 kcal/mol). Ribavirin and tenofovir showed significant binding energy above -8 kcal/mol with seven HB interactions with the main protease and also spike protein. The novel findings regarding the antiviral properties of these dual inhibitors using a computational approach will be a good starting point for the efficacy determination of these drugs for pre-clinical and clinical studies aimed at developing active antivirals to target SARS-CoV-2. Keywords: SARS-CoV-2; FDA-approved drugs; viral inhibitors; in-silico analysis; molecular docking.

Real-World Data Analysis of Efficacy and Survival After Lutetium-177 Labelled PSMA Ligand Therapy in Metastatic Castration-Resistant Prostate Cancer.

BACKGROUND: Lutetium-177 prostate-specific membrane antigen (177Lu-PSMA) radioligand therapy is emerging as a promising treatment for metastatic castration-resistant prostate cancer refractory to established therapies. While there is an increasing body of survival and other data from retrospective analyses and prospective trials, there is no clear understanding of how best to predict therapy response and survival outcomes. OBJECTIVE: In this retrospective cohort analysis, we aimed to identify features that are associated with response to radioligand therapy and greater survival based on analysis of real-world data. PATIENTS AND METHODS: 191 patients aged 70 ± 8 years with metastatic castration-resistant prostate cancer treated with radioligand therapy from November 2015 to February 2019 were included for analysis. Eligible patients had PSMA-expressing metastatic castration-resistant prostate cancer (confirmed by a 68Ga-PSMA-ligand positron emission tomography (PET)/computed tomography (CT) scan), an Eastern Cooperative Oncology Group performance status score ≤ 2 and no significant kidney, liver or bone marrow dysfunction (as characterised by kidney and liver function tests and a full blood count). Patients received one to five cycles of intravenous 177Lu-PSMA-ligand therapy. Endpoints included biochemical [prostate-specific antigen (PSA)] and radiologic (PSMA PET/CT) response, progression-free survival and overall survival, defined according to the Prostate Cancer Working Group 3 guidelines. Survival analysis was conducted by Kaplan-Meier estimation. RESULTS: Most individuals (89.5%) previously underwent first- and second-line systematic therapy. Of the 191 men treated with 452 cycles with mean injected activity of 6.1 ± 1.0 GBq per cycle, 159 patients were assessed for a biochemical response defined as a PSA decline ≥ 50% from baseline. A ≥ 50% PSA decline was observed in 89 (56%) patients, while any PSA decline occurred in 120 (75%) men. For the entire cohort, median values (interquartile range) of overall survival [n = 191], PSA progression-free survival [n = 132] and PET/CT progression-free survival were 12 (5-18), 4 (3-8) and 6 (3-10) months, respectively. Survival analysis confirmed better outcomes in individuals who had demonstrated therapy response. Predominantly lymph node metastatic disease and chemotherapy-naïve status were significant pre-therapy factors associated with longer survival. Baseline PSA was significantly linked to survival outcomes: lower levels predicted a lower risk of death and disease progression. Treatment-related adverse events included grade 3 or 4 haematological (12%), grade 1 or 2 renal (4.5%), and grade 3 or 4 clinical events (5.7%). CONCLUSIONS: Our findings suggest that 177Lu-PSMA radioligand therapy provides a significant response rate with a low toxicity profile. The evidence promotes greater efficacy of radioligand therapy in predominantly lymph node metastatic castration-resistant prostate cancer, and in individuals with chemotherapy-naïve status and lower levels of baseline PSA.

Comparison of Cytokine Expression Profile in Chikungunya and Dengue Co-Infected and Mono-Infected Patients' Samples.

Chikungunya (CHIKV) and Dengue (DENV) viruses cause an acute febrile illness which is hard to clinically differentiate and treat since both exhibit similar symptoms. Hence, this study was aimed at identifying the expression profiles of cytokines on co-infected samples and compare with CHIKV and DENV mono-infected samples. Serum samples of 292 suspected patients during 2009-2011 were analyzed. The presence of primary (IgM)/secondary (IgG) antibodies and early NS1 Dengue antigens were confirmed by capture ELISA. Molecular diagnosis and serotypes were discriminated by RT-PCR, confirmed by sequencing. All the plasma samples were assayed for cytokine expression by BDTM cytometry bead array (CBA) and compared with independent mono-infection viral load. Among the tested samples, 82 were confirmed as Dengue positive; 52 through IgM (17.8%), and 30 through IgG (10.2%). Additionally, 186 samples were confirmed as Chikungunya, 96 through IgM (32.6%) and 92 through IgG (31.5%) ELISA, respectively. Interestingly, 19 patients were co-infection positive in which, only 6 were confirmed for CHIKV and 7 for DENV by RT-PCR. Among 8 cytokines, IL-2, IL-8, IFNα, IFN γ, and IL-12 were found to be significantly different between co-infected and CHIKV mono-infected patients and correlated with viral load. DENV viral load was correlated with cytokine expression and a significant difference in IL-2 and IL-12 was observed between DENV mono-infected and DENV and CHIKV co-infected patients. Results indicated that apart from serological and molecular confirmation, cytokines could be used as a specific biomarker for the diagnosis of DENV and CHIKV. In the future, the role of independent cytokines can be determined to understand the pathogenesis and etiology of these dreadful diseases.

Comprehensive review on the prevailing COVID-19 therapeutics and the potential of repurposing SARS-CoV-1 candidate drugs to target SARS-CoV-2 as a fast-track treatment and prevention option.

The recent seemingly uncontrollable pandemic caused by the novel severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) has been able to spread quickly due to the non-availability of effective antivirals or vaccines. The virus has structural and non-structural proteins that are considered as possible targets. Receptor recognition is the critical determinant and preliminary phase of viral infection to enter the host cell and causes tissue tropism. We have conducted a comprehensive review of relevant publication on in vitro, in silico, in vivo and clinical evaluation of drug candidates ranging from broad-spectrum antivirals to natural molecules targeted towards viral spike protein in addition to evaluate their suitability as therapies based on an analysis of the similarities between SARS-CoV-1 and SARS-CoV-2. In general, antiviral targets are based on two strategies, either targeting the host or the host's immune cell. We have reviewed the available details on the SARS-CoV-2 strain's host-viral binding sites entry mechanism, alongside recently tested effective antivirals. The hypothesis of this review may provide clear insight for researchers and physicians who are struggling to narrow down scientific options to control the current pandemic. Overall, we found that the promising efficacious drug candidates reported against SARS-CoV-1 could be considered for drug repurposing; this might help to identify a potential drug for therapeutic measures and development of vaccine for COVID-19.

Diagnostic and Prognostic Significance of MiR-150 in Colorectal Cancer: A Systematic Review and Meta-Analysis.

Although treatment options have improved, the survival and quality of life of colorectal cancer (CRC) patients remain dismal. Therefore, significant biomarker prediction may help to improve colorectal cancer patient's prognosis profile. MiRNAs have come as an option because of their essential role in cancer initiation and progression by regulating several molecular processes. MiR-150 has different roles in cancer, but its function in CRC is still ambiguous. We undertook a systematic review and meta-analysis according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) research criteria by interrogating several databases in order to assess the diagnostic accuracy and prognostic value of miR-150. Additionally, clinicalgov.org was scanned for possible trials. The literature was screened from inception to February 2020. A total of 12 out of 70 full-text articles were included in the meta-analysis. Among these, nine studies were included for diagnostic accuracy, and the remaining three were considered for prognostic significance of miR-150. With our results, miR-150 is an appropriate diagnostic biomarker, especially in serum and plasma, while the prognostic value of miR-150 was not statistically significant. The present study findings suggest that miR-150 has high specificity and sensitivity values as a potential diagnostic biomarker in colorectal cancer patients.

The Significance of miRNAs as a Prognostic Biomarker for Survival Outcome in T Cell - Acute Lymphoblastic Leukemia Patients: A Systematic Review and Meta-Analysis.

PURPOSE: T-cell acute lymphoblastic leukemia (T-ALL) affects lymphoid cells. Previous studies have reported that miRNAs play a significant role in T-ALL prognosis and have the potential to function as biomarkers in T-ALL. Therefore, this systematic review and meta-analysis study was designed to evaluate the overall prognostic impact of miRNAs in T-ALL patients. METHODS: Eligible studies published between Jan 2010 and April 2018 were retrieved from online bibliographic databases based on multiple keywords to generate search strings. Meta-analysis was performed using the outcome measure, Hazard Ratio (HR). A survival analysis of all studies was conducted and a subsequent forest plot was generated to evaluate the pooled effect size, across all T-ALL patients. Subgroup analysis was conducted based on demographic characteristics and commonly represented miRNAs among the included studies. RESULTS: A total of 17 studies were included for systematic review, among which 16 studies were eligible for meta-analysis, which, in total discussed 32 different miRNAs. The mean effect size of HR value was 0.929 (CI 0.878-0984), which indicates a decrease in risk of death by 7.1%. The analysis was based on the random effects model with the heterogeneity measure index (I2) being 84.92%. The pooled effect size (HR) of upregulated and downregulated miRNA expressions on survival outcome in the T-ALL patient was 0.787 (CI 0.732-0.845) and 1.225 (CI 1.110-1.344) respectively. The subgroup analysis was performed based on demographic characteristics (age, gender, lactate dehydrogenase, WBC count) and expression of miR221 and miR46a. CONCLUSION: Our systematic review and meta-analysis findings suggest that the overall miRNA expression is potentially associated with a decreased likelihood of death in T-ALL patients. Although our findings are inconclusive, the results point toward miRNA expression allowing for prognostic evaluation of T-ALL patients.

Prognostic Value of MicroRNAs in Stage II Colorectal Cancer Patients: A Systematic Review and Meta-Analysis.

BACKGROUND: We performed a systematic review and meta-analysis to identify and underline multiple microRNAs (miRNAs) as biomarkers of disease prognosis in stage II colorectal cancer (CRC) patients. METHODS AND ANALYSIS: This systematic review and meta-analysis study was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The required articles were collected from online bibliographic databases from January 2011 to November 2019 with multiple permutation keywords. Quantitative data synthesis was based on a meta-analysis with pooled data to observe and analyse the outcome measures and effect estimates by using the random effect model. The subgroup analysis was performed from demographic characteristics and the available data. RESULTS: Eighteen articles were included in this study, 16 of which were incorporated for meta-analysis to examine the stage II CRC prognosis with up- and downregulated miRNA expressions. The pooled hazard ratio (HR) for death in stage II CRC patients was 1.90 (95% confidence interval 1.63-2.211), with a significant p value. A subgroup analysis based on up- or downregulated miRNA expression individually and any deregulated miRNA was also associated with a worse prognosis. The subgroup analysis included parameters such as age, gender, stage II and III combined patients' survival and the repetitive miRNAs (miR21, miR215, miR143-5p, miR106a and miR145) individually. CONCLUSION: MicroRNAs play a significant role in determining prognosis in stage II CRC patients, with upregulation of miR21, miR215, miR143-5p and miR106a, in particular, portending a worse prognosis. These miRNAs could be considered for further evaluation as biomarkers of prognosis and to guide the decision to administer adjuvant chemotherapy.

Air pollution enhances susceptibility to novel coronavirus (COVID-19) infection - an impact study.

On concurring to the current evidence, the myriad of vulnerable COVID-19 (Coronavirus Disease 19) transmission is acquiring through human-to-human transmission through droplets, which is depicting devastating pandemic. Urbanization and industrialization are the major contributing factors to the on-going change in global climate, with increased air pollution and poor air quality. As the global climate and air quality deteriorate, air pollutants remain as a fundamental concern to public health. Air pollution has been globally acknowledged as a major influence and exacerbating factor for human morbidity and mortality influenced on various respiratory diseases such as lung cancer, bronchitis, chronic obstructive pulmonary diseases, pneumonia, asthma, and influenza. Patients by long - term exposure to polluted air leads to chronic lung and heart conditions are less able to fight off lung infections and likely to die. Polluted air in developed countries is causing heart and lung damage and is responsible for early deaths in a year. This is also likely the case for COVID-19. The more severe impact by COVID-19 on city dwellers and those exposed to toxic fumes leads to the primary health damage such as respiratory infections than on others. The health damage inflicted on people by long-standing air pollution in cities is likely to increase the death rate by COVID-19. By lowering air pollution levels probability to reduce the spread of most vulnerable viruses by aerosol to fight against any possible future pandemics.

Clinical Theragnostic Relationship between Drug-Resistance Specific miRNA Expressions, Chemotherapeutic Resistance, and Sensitivity in Breast Cancer: A Systematic Review and Meta-Analysis.

Awareness of breast cancer has been increasing due to early detection, but the advanced disease has limited treatment options. There has been growing evidence on the role of miRNAs involved in regulating the resistance in several cancers. We performed a comprehensive systematic review and meta-analysis on the role of miRNAs in influencing the chemoresistance and sensitivity of breast cancer. A bibliographic search was performed in PubMed and Science Direct based on the search strategy, and studies published until December 2018 were retrieved. The eligible studies were included based on the selection criteria, and a detailed systematic review and meta-analysis were performed based on PRISMA guidelines. A random-effects model was utilised to evaluate the combined effect size of the obtained hazard ratio and 95% confidence intervals from the eligible studies. Publication bias was assessed with Cochran's Q test, I2 statistic, Orwin and Classic fail-safe N test, Begg and Mazumdar rank correlation test, Duval and Tweedie trim and fill calculation and the Egger's bias indicator. A total of 4584 potential studies were screened. Of these, 85 articles were eligible for our systematic review and meta-analysis. In the 85 studies, 188 different miRNAs were studied, of which 96 were upregulated, 87 were downregulated and 5 were not involved in regulation. Overall, 24 drugs were used for treatment, with doxorubicin being prominently reported in 15 studies followed by Paclitaxel in 11 studies, and 5 drugs were used in combinations. We found only two significant HR values from the studies (miR-125b and miR-4443) and our meta-analysis results yielded a combined HR value of 0.748 with a 95% confidence interval of 0.508-1.100; p-value of 0.140. In conclusion, our results suggest there are different miRNAs involved in the regulation of chemoresistance through diverse drug genetic targets. These biomarkers play a crucial role in guiding the effective diagnostic and prognostic efficiency of breast cancer. The screening of miRNAs as a theragnostic biomarker must be brought into regular practice for all diseases. We anticipate that our study serves as a reference in framing future studies and clinical trials for utilising miRNAs and their respective drug targets.

Prognostic Significance of FOXC1 in Various Cancers: A Systematic Review and Meta-Analysis.

BACKGROUND: Forkhead box C1 (FOXC1), a member of the Forkhead box (Fox) transcription factor family, plays an essential role in lymphatic vessel formation, angiogenesis and metastasis. Observational studies examining the relationship between the protein biomarker FOXC1 and breast cancer prognosis have reported conflicting findings. This systematic review and meta-analysis evaluates the prognostic value of the FOXC1 expression in association with patient survival in breast cancer and other types of cancers in order to identify the overall prognostic effectiveness of FOXC1. METHODS: This study followed the guidelines established in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). We conducted a broad search on the online bibliographic databases EMBASE, PubMed, Science Direct and Scopus, limiting search to publications from 2010 to 2018. The prognostic value was demonstrated by a random effects model meta-analysis using the hazard ratio (HR) with 95% confidence interval (CI) for overall survival (OS) in various cancer patients. The heterogeneity was measured by the I2 statistic. Publication bias and quality assessment for the selected articles was performed. Subgroup analysis was conducted based on the data available from the selected articles. RESULTS: A total of 16 studies met the predefined selection criteria established for our systematic review and meta-analysis, with multiple studies using diverse methodologies and reported on differing clinical outcomes, falling under a common banner of FOXC1 expression and survival in cancer. Overall, we observed a statistically non-significant association between FOXC1 protein expression and patients survival (HR: 1.186 and 95% CI 1.122-1.255, p = 0.000, I2 = 88.83%). CONCLUSION: In summary, FOXC1 protein expression indicated poor survival outcome in various carcinomas, especially in patients with breast cancer, suggesting it as a possible biomarker for the prognosis in multiple carcinomas. Further clinical evaluation and large-scale cohort studies are required to accurately identify its possible clinical utility.

Diagnostic and prognostic role of HE4 expression in multiple carcinomas: A protocol for systematic review and meta-analysis.

BACKGROUND: Human epididymis protein 4 (HE4) protein has garnered a great degree of interest as a complementary biomarker to carbohydrate antigen 125 (CA125), or even as an independent biomarker for monitoring, diagnosis, and prognostication of ovarian cancer. Its use is currently limited to ovarian cancer. Recent studies have suggested that it could also be used in other types of cancers. METHODS: The Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) guidelines was used to design this meta-analysis protocol. The final study will also be conducted under the PRISMA guidelines for systematic reviews and meta-analyses. The core bibliographic database search will be carried out by 2 reviewers working individually, with each conducting an initial screening based on titles and abstracts. The shortlisted articles will be selected for review and statistical analysis based on predefined inclusion and exclusion criteria. Study characteristics, relevant clinicopathological characteristics and statistical data required for meta-analysis (hazard ratios [HRs] and 95% confidence interval [CIs) will be extracted and compiled into a MS Excel datasheet. Meta-analysis will be performed, using a random-effects model, and the results (pooled HR and 95% CI) will be presented in the form of a forest plot. Publication bias will also be assessed by use of Egger bias indicator test and funnel plot symmetry. If data are insufficient, a narrative line of review will be pursued. DISCUSSION: HE4 protein has been shown to have great potential for clinical use as a diagnostic and prognostic marker in epithelial ovarian cancer (EOC). However, HE4 is not only limited to expression in ovarian cancer, but is also overexpressed in lung and endometrial cancers. The effectiveness of HE4 as a biomarker in cancers (other than EOC) has not yet been studied in the form of a comprehensive systematic review and meta-analysis. The results of this study should allow for expanded use of HE4 as a multiutility biomarker in multiple cancer types, thereby, elevating HE4's value as a cancer biomarker. PROSPERO REGISTRATION: CRD42019120326.

Prognostic Value of miRNAs in Head and Neck Cancers: A Comprehensive Systematic and Meta-Analysis.

Head and Neck Cancer (HNC) is the sixth most common type of cancer across the globe, with more than 300,000 deaths each year, globally. However, there are currently no standardised molecular markers that assist in determining HNC prognosis. The literature for this systematic review and meta-analysis were sourced from multiple bibliographic databases. This review followed PRISMA guidelines. The Hazard Ratio (HR) was selected as the effect size metric to independently assess overall survival (OS), disease-free survival (DFS), and prognosis. Subgroup analysis was performed for individual highly represented miRNA. A total of 6843 patients across 50 studies were included in the systematic review and 34 studies were included in the meta-analysis. Studies across 12 countries were assessed, with China representing 36.7% of all included studies. The analysis of the survival endpoints of OS and DFS were conducted separately, with the overall pooled effect size (HR) for each being 1.825 (95% CI 1.527-2.181; p < 0.05) and 2.596 (95% CI 1.917-3.515; p < 0.05), respectively. Subgroup analysis was conducted for impact of miR-21, 200b, 155, 18a, 34c-5p, 125b, 20a and 375 on OS, and miR-21 and 34a on DFS. The pooled results were found to be statistically significant for both OS and DFS. The meta-analysis indicated that miRNA alterations can account for an 82.5% decrease in OS probability and a 159.6% decrease in DFS probability. These results indicate that miRNAs have potential clinical value as prognostic biomarkers in HNC, with miR-21, 125b, 34c-5p and 18a, in particular, showing great potential as prognostic molecular markers. Further large scale cohort studies focusing on these miRNAs are recommended to verify the clinical utility of these markers individually and/or in combination.

Prognostic significance of blood inflammatory biomarkers NLR, PLR, and LMR in cancer-A protocol for systematic review and meta-analysis.

BACKGROUND: The neutrophil-lymphocyte-ratio, platelet-lymphocyte-ratio, and monocyte-lymphocyte-ratio have been explored as a simple, inexpensive, and effective method for cancer prognosis. However, there are no studies that have investigated the comparative utility of these markers, in multiple cancers. METHODS: The preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) guidelines were used to design this meta-analysis protocol. The final study will also be conducted under the PRISMA guidelines for systematic reviews and meta-analyses. The core bibliographic database search will be carried out by 2 reviewers working individually, with each conducting an initial screening based on titles and abstracts. The shortlisted articles will be selected for review and quantitative analysis, based on predefined inclusion and exclusion criteria. Study characteristics, relevant clinicopathological characteristics, and statistical data required for meta-analysis (hazard ratios [HRs] and 95% confidence intervals [CIs]) will be extracted and compiled into a MS Excel datasheet. Meta-analysis will be performed, using a random-effects model, and the results (pooled HR and 95% CI) will be presented in the form of a forest plot. Publication bias will also be assessed by use of Egger bias indicator test and funnel plot symmetry. If statistical data from included studies is insufficient, a qualitative literature review will be pursued.PROSPERO registration: PROSPERO CRD42019121008.

miRNA Predictors of Pancreatic Cancer Chemotherapeutic Response: A Systematic Review and Meta-Analysis.

BACKGROUND: pancreatic cancer (PC) has increasing incidence and mortality in developing countries, and drug resistance is a significant hindrance to the efficacy of successful treatment. The objective of this systematic review and meta-analysis was to evaluate the association between miRNAs and response to chemotherapy in pancreatic cancer patients. METHODS: the systematic review and meta-analysis was based on articles collected from a thorough search of PubMed and Science Direct databases for publications spanning from January 2008 to December 2018. The articles were screened via a set of inclusion and exclusion criteria based on the preferred reporting items for systematic review and meta-analysis (PRISMA) guidelines. Data was extracted, collated and tabulated in MS Excel for further synthesis. Hazard ratio (HR) was selected as the effect size metric to be pooled across studies for the meta-analysis, with the random effects model being applied. Subgroup analysis was also conducted, and the presence of publication bias in the selected studies was assessed. Publication bias of the included studies was quantified. FINDINGS: of the 169 articles screened, 43 studies were included in our systematic review and 13 articles were included in the meta-analysis. Gemcitabine was observed to be the principal drug used in a majority of the studies. A total of 48 miRNAs have been studied, and 18 were observed to have possible contributions to chemoresistance, while 15 were observed to have possible contributions to chemosensitivity. 41 drug-related genetic pathways have been identified, through which the highlighted miRNA may be affecting chemosensitivity/resistance. The pooled HR value for overall survival was 1.603; (95% Confidence Interval (CI) 1.2-2.143; p-value: 0.01), with the subgroup analysis for miR-21 showing HR for resistance of 2.061; 95% CI 1.195-3.556; p-value: 0.09. INTERPRETATION: our results highlight multiple miRNAs that have possible associations with modulation of chemotherapy response in pancreatic cancer patients. Further studies are needed to discover the molecular mechanisms underlying these associations before they can be suggested for use as biomarkers of response to chemotherapeutic interventions in pancreatic cancer.