CAR T therapies in multiple myeloma: unleashing the future.

In recent years, the field of cancer treatment has witnessed remarkable breakthroughs that have revolutionized the landscape of care for cancer patients. While traditional pillars such as surgery, chemotherapy, and radiation therapy have long been available, a cutting-edge therapeutic approach called CAR T-cell therapy has emerged as a game-changer in treating multiple myeloma (MM). This novel treatment method complements options like autologous stem cell transplants and immunomodulatory medications, such as proteasome inhibitors, by utilizing protein complexes or anti-CD38 antibodies with potent complement-dependent cytotoxic effects. Despite the challenges and obstacles associated with these treatments, the recent approval of the second FDA multiple myeloma CAR T-cell therapy has sparked immense promise in the field. Thus far, the results indicate its potential as a highly effective therapeutic solution. Moreover, ongoing preclinical and clinical trials are exploring the capabilities of CAR T-cells in targeting specific antigens on myeloma cells, offering hope for patients with relapsed/refractory MM (RRMM). These advancements have shown the potential for CAR T cell-based medicines or combination therapies to elicit greater treatment responses and minimize side effects. In this context, it is crucial to delve into the history and functions of CAR T-cells while acknowledging their limitations. We can strategize and develop innovative approaches to overcome these barriers by understanding their challenges. This article aims to provide insights into the application of CAR T-cells in treating MM, shedding light on their potential, limitations, and strategies employed to enhance their efficacy.

Using machine learning approach for screening metastatic biomarkers in colorectal cancer and predictive modeling with experimental validation.

Colorectal cancer (CRC) liver metastasis accounts for the majority of fatalities associated with CRC. Early detection of metastasis is crucial for improving patient outcomes but can be delayed due to a lack of symptoms. In this research, we aimed to investigate CRC metastasis-related biomarkers by employing a machine learning (ML) approach and experimental validation. The gene expression profile of CRC patients with liver metastasis was obtained using the GSE41568 dataset, and the differentially expressed genes between primary and metastatic samples were screened. Subsequently, we carried out feature selection to identify the most relevant DEGs using LASSO and Penalized-SVM methods. DEGs commonly selected by these methods were selected for further analysis. Finally, the experimental validation was done through qRT-PCR. 11 genes were commonly selected by LASSO and P-SVM algorithms, among which seven had prognostic value in colorectal cancer. It was found that the expression of the MMP3 gene decreases in stage IV of colorectal cancer compared to other stages (P value < 0.01). Also, the expression level of the WNT11 gene was observed to increase significantly in this stage (P value < 0.001). It was also found that the expression of WNT5a, TNFSF11, and MMP3 is significantly lower, and the expression level of WNT11 is significantly higher in liver metastasis samples compared to primary tumors. In summary, this study has identified a set of potential biomarkers for CRC metastasis using ML algorithms. The findings of this research may provide new insights into identifying biomarkers for CRC metastasis and may potentially lay the groundwork for innovative therapeutic strategies for treatment of this disease.

Evaluation of the Relationship between Family History and Occurrence, Anatomical Location, and Extent of Coronary Artery Disease among Patients Undergoing Coronary Angiography.

Background: A positive family history (FH) of coronary artery disease (CAD) is considered an independent risk factor for developing CAD. However, the relationship between the occurrence, angiographic anatomical location of the stenosis, and extent of CAD and the risk factors in the patients and their relatives is not well defined. Evaluation of this relationship is our main goal in this study. Methods: In this descriptive cross-sectional study, the FH data for CAD and premature death in first-and second-degree relatives, angiographic anatomical location of the stenosis, the extent of CAD in the patients and their relatives, as well as the relationship between other risk factors and the extent of CAD, were collected from 300 adult patients undergoing coronary angiography at Farshchian cardiovascular hospital in Hamadan (Iran) between March 2020 and 2021. SPSS 24 and the chi-square, Fisher exact, and student t tests were used to analyze data. The significance level was considered P < 0.05. Results: Out of 300 patients, 185 (61.7%) were men and 115 (38.3%) were women. A total of 177 patients (59%) in maternal and 82 patients (27.3%) in paternal relatives had an FH of CAD. There was a significant relationship between the severity of coronary artery involvement and risk factors (P < 0.001). Moreover, there was no significant relationship between the location of coronary artery involvement of the right coronary artery, left coronary artery, and left anterior descending artery and the severity of involvement of patients undergoing coronary angiography and their first- and second-degree relatives (P = 0.480). Conclusion: Our findings suggest that there was no significant relationship between the anatomical location of the stenosis and the number of vessels involved and the FH of the patients. In patients with an FH, the extent of CAD significantly increased according to their risk factors for heart disease.

Kugel's Artery as a Rare Intracoronary Collateralization Does Not Effectively Guarantee the Presence of Viable Hibernating Myocardium.

In this note, it was aimed to describe a 66-year-old patient for ischemia evaluation following the episodes of chest discomfort using dipyridamole stress-rest myocardial perfusion single-photon emission computed tomography (SPECT). Invasive coronary angiography demonstrated a total occlusion of the right coronary artery (RCA) and prominent RCA intracoronary collateral (Kugel's artery) associated with nonviable, infarcted myocardium in the inferior wall of left ventricular LV on myocardial perfusion SPECT. Thus, recanalization of RCA was not performed in our patient. It is concluded that performing complementary imaging modalities for assessing myocardial perfusion like SPECT for the prediction of viability to sole reliance on angiographic data in decision making for revascularization is encouraged.

Multifunctional nanostructures: Intelligent design to overcome biological barriers.

Over the past three decades, nanoscience has offered a unique solution for reducing the systemic toxicity of chemotherapy drugs and for increasing drug therapeutic efficiency. However, the poor accumulation and pharmacokinetics of nanoparticles are some of the key reasons for their slow translation into the clinic. The is intimately linked to the non-biological nature of nanoparticles and the aberrant features of solid cancer, which together significantly compromise nanoparticle delivery. New findings on the unique properties of tumors and their interactions with nanoparticles and the human body suggest that, contrary to what was long-believed, tumor features may be more mirage than miracle, as the enhanced permeability and retention based efficacy is estimated to be as low as 1%. In this review, we highlight the current barriers and available solutions to pave the way for approved nanoformulations. Furthermore, we aim to discuss the main solutions to solve inefficient drug delivery with the use of nanobioengineering of nanocarriers and the tumor environment. Finally, we will discuss the suggested strategies to overcome two or more biological barriers with one nanocarrier. The variety of design formats, applications and implications of each of these methods will also be evaluated.

Molecular imprinting of miR-559 on a peptide-immobilized poly L-DOPA/silica core-shell and in vitro investigating its effects on HER2-positive breast cancer cells.

In a significant percentage of breast cancers, increased expression of the HER2 receptor is seen and is associated with the spread and worsening of the disease. This research aims to investigate the effect of miR-559 (which targets HER2 mRNA) on SKBR3 breast cancer cells and the possibility of their effective delivery with polymeric nanoparticles and tumor-targeting peptides. L-DOPA monomers were polymerized on the surface of silica nanoparticles in the presence of miR-559 (as a molecular template for molecular imprinting) then an anti-HER2 peptide coupled to the surface of these polymeric nanocomposites (miR-NC-NL2), and the effects of this construct against a HER2-positive breast cancer cells (SKBR3 cells) investigated in vitro conditions. The results showed that miR-NC-NL2 is selective for HER2-positive cells and delivers the miR-559 to them in a targeted manner. miR-NC-NL2 decreased the proliferation of SKBR3 cells and reduced the expression and production of HER2 protein in these cells. Effective and targeted delivery of miR-559 to HER2-positive cancer cells by the miR-NC-NL2 promises the therapeutic potential of this nascent structure based on its inhibitory effect on cancer growth and progression. Of course, animal experiments require a better understanding of this structure's anti-tumor effects.

Evaluation of the Effect of Chelating Arms and Carrier Agents on t he Radiotoxicity of TAT Agents.

Targeted Alpha Therapy (TAT) is considered an evolving therapeutic option for cancer cells, in which a carrier molecule labeling with an α-emitter radionuclide make the bond with a specific functional or molecular target. α-particles with high Linear Energy Transfer (LET) own an increased Relative Biological Effectiveness (RBE) over common ß-emitting radionuclides. Normal tissue toxicity due to non-specific uptake of mother and daughter α-emitter radionuclides seems to be the main conflict in clinical applications. The present survey reviews the available preclinical and clinical studies investigating healthy tissue toxicity of the applicable α -emitters and particular strategies proposed for optimizing targeted alpha therapy success in cancer patients.

Effects of coenzyme Q10 supplementation on oxidative stress biomarkers following reperfusion in STEMI patients undergoing primary percutaneous coronary intervention.

Introduction: It is well-established that oxidative stress is deeply involved in myocardial ischemia-reperfusion injury. Considering the potent antioxidant properties of coenzyme Q10 (CoQ10), we aimed to assess whether CoQ10 supplementation could exert beneficial effects on plasma levels of oxidative stress biomarkers in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPIC). Methods: Seventy patients with the first attack of STEMI, eligible for PPCI were randomly assigned to receive either standard treatments plus CoQ10 (400 mg before PPCI and 200 mg twice daily for three days after PPCI) or standard treatments plus placebo. Plasma levels of oxidative stress biomarkers, including superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), total antioxidant capacity (TAC), and malondialdehyde (MDA) were measured at 6, 24, and 72 hours after completion of PPCI. Results: The changes in plasma levels of the studied biomarkers at 6 and 24 hours after PPCI were similar in the both groups (P values>0.05). This is while at 72 hours, the CoQ10- treated group exhibited significantly higher plasma levels of SOD (P value<0.001), CAT (P value=0.001), and TAC (P value<0.001), along with a lower plasma level of MDA (P value=0.002) compared to the placebo-treated group. The plasma activity of GPX showed no significant difference between the groups at all the study time points (P values>0.05). Conclusion: This study showed that CoQ10 has the potential to modulate the balance between antioxidant and oxidant biomarkers after reperfusion therapy. Our results suggest that CoQ10, through its antioxidant capacity, may help reduce the reperfusion injury in ischemic myocardium.

Relationship between Calcium Score and Conventional Risk Factors in the Diagnosis of Atherosclerosis.

Background: The coronary artery calcium score has been established as a highly specific feature of coronary atherosclerosis. The present study aimed to assess the possible association of coronary artery risk factors involving atherosclerosis with the coronary artery calcification (CAC) scores using coronary computed tomographic angiography (CCTA). Methods: The present cross-sectional study, performed on 252 patients in need of CCTA during April 2019 and September 2019 at Farshchian hospital in Hamadan, Iran. The demographic information and risk factors were acquired from the files of patients. Furthermore, the CACs of patients were calculated and expressed as the Agatston score. Based on the Agatston scale, participants were divided into 4 CAC scores: zero (CAC = 0), mild (CAC = 1-99), moderate (CAC = 100-399), and severe (CAC ≥400). The association between possible coronary artery disease (CAD) risk variables and the CAC score was investigated using multinomial logistic regression. Results: Of 252 participants, approximately 40% of studied patients had a positive CAC score (CAC > 0). CAC significantly shifts toward higher scores in smokers, patients with diabetes, hypertension, and older patients. Mild (CAC = 1-99) and moderate CAC (100-399) were significantly associated with diabetes (odds ratio [OR], 3.26; 95% CI, 1.48-7.17) and (OR, 12; 95% CI, 4.40-32.71) for mild and moderate CAC, respectively. However, the strongest predictor for severe CAC was diabetes (OR, 7.72; 95% CI, 2.10-28.35). Conclusion: Coronary artery calcium scoring is a marker for risk factors associated with atherosclerosis. In this study, more than half of patients in CAC screening had CAC = 0. The strongest predictor of severe CAC>0 was smoking and diabetes. Regarding this association between health condition and CAC, determining the CAC can prevent major coronary heart disease events in these patients.

Ferroptosis Inhibitors as Potential New Therapeutic Targets for Cardiovascular Disease.

Ferroptosis is a novel form of programmed cell death that occurs due to an increase in iron levels. Ferroptosis is implicated in a number of cardiovascular diseases, including myocardial infarction (MI), reperfusion damage, and heart failure (HF). As cardiomyocyte depletion is the leading cause of patient morbidity and mortality, it is critical to thoroughly comprehend the regulatory mechanisms of ferroptosis activation. In fact, inhibiting cardiac ferroptosis can be a useful therapeutic method for cardiovascular disorders. The iron, lipid, amino acid, and glutathione metabolisms strictly govern the beginning and execution of ferroptosis. Therefore, ferroptosis can be inhibited by iron chelators, free radical-trapping antioxidants, GPX4 (Glutathione Peroxidase 4) activators, and lipid peroxidation (LPO) inhibitors. However, the search for new molecular targets for ferroptosis is becoming increasingly important in cardiovascular disease research. In this review, we address the importance of ferroptosis in various cardiovascular illnesses, provide an update on current information regarding the molecular mechanisms that drive ferroptosis, and discuss the role of ferroptosis inhibitors in cardiovascular disease.

Oral N-acetylcysteine as an adjunct to standard medical therapy improved heart function in cases with stable class II and III systolic heart failure.

BACKGROUND: This research attempted to assess whether N-acetylcysteine (NAC) as adjunctive therapy can be useful in the treatment of patients with heart failure (HF). METHODS: Fifty-five cases with diagnosed systolic HF and stable symptomatic New York Heart Association (NYHA) functional class II and III and on optimal medical treatment of HF for at least 3 months were assigned for receiving oral NAC (600 mg twice daily) or placebo for 12 weeks. The outcomes were changes in the echocardiographic hemodynamic indices as well as the patients' functional capacity assessed by NYHA classification over a 12-week treatment. RESULTS: Compared to placebo, NAC more significantly improved the systolic left ventricular (LV) function expressed as the ejection fraction and Tei index. These changes are accompanied by more improvement in other LV echocardiographic indices including LV end-diastolic volume index and LV global longitudinal strain in the patients receiving NAC in comparison with those receiving placebo. In parallel with the improvement of LV function, right ventricular (RV) function expressed as RV fractional area change and RV Tei-index also got more improvement in those receiving NAC than those receiving placebo. However, the change in RV global longitudinal strain did not show a significant difference between study groups. Additionally, at week 12, the distribution of the NYHA functional class also shifted toward a better outcome in the NAC group in comparison with the placebo group; however, it was not significant. CONCLUSIONS: These preliminary data support experimental findings showing that NAC supplementation is able to improve heart function. TRIAL REGISTRATION: The registration of the trial was done at the Iranian Registry of Clinical Trials ( www.irct.ir ). Identifier code: IRCT20120215009014N333. Registration date: 2020-01-11.

FLVCR1-AS1 and FBXL19-AS1: Two Putative lncRNA Candidates in Multiple Human Cancers.

(1) Background: Mounting evidence supports the idea that one of the most critical agents in controlling gene expression could be long non-coding RNAs (lncRNAs). Upregulation of lncRNA is observed in the different processes related to pathologies, such as tumor occurrence and development. Among the crescent number of lncRNAs discovered, FLVCR1-AS1 and FBXL19-AS1 have been identified as oncogenes in many cancer progression and prognosis types, including cholangiocarcinoma, gastric cancer, glioma and glioblastoma, hepatocellular carcinoma, lung cancer, ovarian cancer, breast cancer, colorectal cancer, and osteosarcoma. Therefore, abnormal FBXL19-AS1 and FLVCR1-AS1 expression affect a variety of cellular activities, including metastasis, aggressiveness, and proliferation; (2) Methods: This study was searched via PubMed and Google Scholar databases until May 2022; (3) Results: FLVCR1-AS1 and FBXL19-AS1 participate in tumorigenesis and have an active role in impacting several signaling pathways that regulate cell proliferation, migration, invasion, metastasis, and EMT; (4) Conclusions: Our review focuses on the possible molecular mechanisms in a variety of cancers regulated by FLVCR1-AS1 and FBXL19-AS1. It is not surprising that there has been significant interest in the possibility that these lncRNAs might be used as biomarkers for diagnosis or as a target to improve a broader range of cancers in the future.

Investigating the relationship between the severity of coronary artery disease and inflammatory factors of MHR, PHR, NHR, and IL-25.

Background: Coronary artery disease (CAD), as a most common cause of death, is mainly caused by atherosclerosis. Due to the role of inflammation in the process of atherosclerosis, in the present study, the relationship between the severity of coronary artery disease and inflammatory factors of monocyte to HDL-C ratio (MHR), platelet-to-HDL-C ratio (PHR), neutrophil to HDL-C ratio (NHR), and IL-25 was investigated. Methods: In this cross-sectional study, 64 patients with diagnosis of coronary artery disease who were undergoing angiography in Farshchian heart center in Hamadan were studied. For each patient, the count of monocytes, neutrophils, platelet, and HDL-C, and IL-25 were measured from their blood and serum samples. Also, demographic information, such as age, gender, diabetes, smoking, and history of hypertension, was collected using a checklist. Data were described using frequency, percent, mean, and standard deviation. Statistical analysis was performed using independent t test, Mann-Whitney, Wilcoxon, and Spearman rank correlation tests, and multiple linear regression by SPSS version 25.0 SPSS Inc). P <.05 was considered as significant. Results: The results of this study showed that IL-25 and MHR index has a significant correlation with coronary artery disease and Gensini score (P ˂.001). The PHR index was associated with coronary artery disease. Also, qualitative variables, such as history of hypertension, history of smoking, and gender, have a significant association with the severity of coronary artery disease (P <.05). Conclusion: Among the inflammatory markers examined, IL-25 and MHR are stronger markers for assessing the severity of coronary artery disease. Simple and available IL-25 and MHR measurements may be able to, along with common risk factors and lipid profiles, predict the amount of vascular occlusion in treatment centers as an alternative of angiography as well as screening high risk patients prone to cardiovascular disease.

Roles of miRNAs in Colorectal Cancer: Therapeutic Implications and Clinical Opportunities.

Colorectal cancer (CRC) is one of the most disseminated diseases across the globe engaging the digestive system. Various therapeutic methods from traditional to the state-of-the-art ones have been applied in CRC patients, however, the attempts have been unfortunate to lead to a definite cure. MiRNAs are a smart group of non-coding RNAs having the capabilities of regulating and controlling coding genes. By utilizing this stock-in-trade biomolecules, not only disease's symptoms can be eliminated, there may also be a good chance for the complete cure of the disease in the near future. Herein, we provide a comprehensive review delineating the therapeutic relationship between miRNAs and CRC. To this, various clinical aspects of miRNAs which act as a tumor suppressor and/or an oncogene, their underlying cellular processes and clinical outcomes, and, in particular, their effects and expression level changes in patients treated with chemo- and radiotherapy are discussed. Finally, based on the results deducted from scientific research studies, therapeutic opportunities based on targeting/utilizing miRNAs in the preclinical as well as clinical settings are highlighted.

Very Early Discharge of Patients with ST-Segment-Elevation Myocardial Infarction after Primary Percutaneous Coronary Intervention.

Background: The discharge of uncomplicated patients with ST-segment-elevation myocardial infarction (STEMI) within 48 to 72 hours has been proven safe and feasible. The safety and feasibility of the very early discharge (≤48 h) of such patients, especially during the COVID-19 pandemic with limited bed availability and infection risk, have yet to be evaluated. Methods: In this cohort study on 108 patients with STEMI who presented to Farshchian Heart Center between February and May 2020, 30 patients received fibrinolysis and 78 were scheduled for emergent coronary angiography. One patient had no coronary obstruction, 3 underwent emergent surgery, and 3 had high-risk features mandating a prolonged stay. The remaining patients were assigned to either Group A (≤48 h) or Group B (>48 h) regarding hospital discharge. Demographic, angiographic, procedural, and outcome data were compared between the 2 groups. Results: Group A consisted of 51 patients, including 7 women (13.7%), at a mean age of 62.74±12.35 years, and Group B comprised 20 patients, including 4 women (20.0%), at a mean age of 65.20±12.82 years. The mean hospital length of stay was 38.02±9.15 hours in Group A and 88.20±23.31 hours in Group B (P<0.001). The mean stent diameter was smaller in Group B (3.19±0.34 mm vs 2.96±0.29 mm; P=0.008). Demographic, angiographic, procedural, and outcome data, including the rates of in-hospital, 1-week, and 1-month mortality, were similar between the 2 groups. Conclusion: This study shows that a hospital discharge in less than 48 hours in low-risk patients with STEMI is safe and feasible. The potential advantages of this approach in the COVID-19 pandemic should be balanced against its risks.

Association of Domestic Physical Violence With Feto-Infant Outcomes in Afghanistan.

Our study aimed to investigate the association between domestic physical violence in pregnancy and feto-infant outcomes among Afghan women. Our study design was a cross-sectional study that utilized secondary data from the 2015 Afghanistan Demographic and Health Survey conducted in 33 provinces of Afghanistan (n = 19 676). We used multiple logistic regression models to evaluate the relationship between domestic violence and early-pregnancy loss, perinatal, and neonatal mortality, with adjustments for confounders. Our results indicate that approximately 16.66% (n = 3278) of Afghan women experienced domestic violence while pregnant. In the adjusted models, we found that domestic physical violence in pregnancy was significantly associated with early-pregnancy loss (adjusted odds ratio [AOR] = 1.58, 95% confidence interval [CI] = 1.32-1.88), but not with perinatal mortality (AOR = 1.12, 95% CI = 0.96-1.32) and neonatal mortality (AOR = 1.10, 95% CI = 0.95-1.28). The higher odds of adverse birth outcomes among victims of domestic violence underlines the necessity for interventions to address violence against women in Afghanistan.