Recent advances in breast cancer metastasis with special emphasis on metastasis to the brain.

Understanding the underlying mechanisms of breast cancer metastasis is of vital importance for developing treatment approaches. This review emphasizes contemporary breakthrough studies with special focus on breast cancer brain metastasis. Acquired mutational changes in metastatic lesions are often distinct from the primary tumor, suggesting altered mutagenesis pathways. The concept of micrometastases and heterogeneity within the tumors unravels novel therapeutic targets at genomic and molecular levels through epigenetic and proteomic profiling. Several pre-clinical studies have identified mechanisms involving the immune system, where tumor associated macrophages are key players. Expression of cell proteins like Syndecan1, fatty acid-binding protein 7 and tropomyosin kinase receptor B have been implicated in aiding the transmigration of breast cancer cells to the brain. Changes in the proteomic landscape of the blood-brain-barrier show altered permeability characteristics, supporting entry of cancer cells. Findings from laboratory studies pave the path for the emergence of new biomarkers, especially blood-based miRNA and circulating tumor cell markers for prognostic staging. The constantly evolving therapeutics call for clinical trials backing supportive evidence of efficacies of both novel and existing approaches. The challenge lying ahead is discovering innovative techniques to replace use of human samples and optimize small-scale patient recruitment in trials.

Prognostic value of liver metastases in colorectal cancer treated by systemic therapy: An ARCAD pooled analysis.

BACKGROUND: The liver is the most frequent site of metastases in colorectal cancer (CRC). This study aimed to assess the response rate and survival outcomes in metastatic CRC patients with non-liver metastases (NLM) compared to those with liver metastases (LM) across different lines of treatment. METHODS: A total of 17,924 mCRC patients included in 26 trials from the ARCAD CRC database were analyzed. The analysis was conducted based on the presence or absence of LM across different treatment groups: chemotherapy (CT) alone, CT + anti-VEGF, CT + anti-EGFR in KRAS wild-type tumors, within the first-line (1 L) and second-line (2 L), and patients enrolled in third-line (≥3 L) trials treated with trifluridine/tipiracil or regorafenib or placebo. The endpoints were overall survival (OS), progression-free survival (PFS), and overall response rate (ORR). RESULTS: Out of the 17,924 patients, 14,066 had LM (30.6 % with only liver involvement and 69.4 % with liver and other metastatic sites), while 3858 patients had NLM. In the CT alone and CT + anti-VEGF subgroups, NLM patients showed better OS and PFS in the 1 L and 2 L settings. However, in the CT + anti-EGFR 1 L and 2 L subgroups, there was no significant difference in OS and PFS between NLM and LM patients. In the ≥ 3 L subgroups, better OS and PFS were observed in NLM patients. ORRs were higher in LM patients than in NLM patients across all cohorts treated in the 1 L and only in the anti-EGFR cohort in the 2 L. CONCLUSION: LM is a poor prognostic factor for mCRC increasing from 1 L to ≥ 3 L except for patients in 1 L and 2 L receiving CT+anti-EGFR. These data justify using LM as a stratification factor in future trials for patients with unresectable mCRC.

Onvansertib in Combination with FOLFIRI and Bevacizumab in Second-Line Treatment of KRAS-Mutant Metastatic Colorectal Cancer: A Phase Ib Clinical Study.

PURPOSE: Onvansertib is a highly specific inhibitor of polo-like kinase 1 (PLK1), with demonstrated safety in solid tumors. We evaluated, preclinically and clinically, the potential of onvansertib in combination with chemotherapy as a therapeutic option for KRAS-mutant colorectal cancer. PATIENTS AND METHODS: Preclinical activity of onvansertib was assessed (i) in vitro in KRAS wild-type and -mutant isogenic colorectal cancer cells and (ii) in vivo, in combination with irinotecan, in a KRAS-mutant xenograft model. Clinically, a phase Ib trial was conducted to investigate onvansertib at doses 12, 15, and 18 mg/m2 (days 1-5 and 14-19 of a 28-day cycle) in combination with FOLFIRI/bevacizumab (days 1 and 15) in patients with KRAS-mutant metastatic colorectal cancer who had prior oxaliplatin exposure. Safety, efficacy, and changes in circulating tumor DNA (ctDNA) were assessed. RESULTS: In preclinical models, onvansertib displayed superior activity in KRAS-mutant than wild-type isogenic colorectal cancer cells and demonstrated potent antitumor activity in combination with irinotecan in vivo. Eighteen patients enrolled in the phase Ib study. Onvansertib recommended phase II dose was established at 15 mg/m2. Grade 3 and 4 adverse events (AE) represented 15% of all treatment-related AEs, with neutropenia being the most common. Partial responses were observed in 44% of patients, with a median duration of response of 9.5 months. Early ctDNA dynamics were predictive of treatment efficacy. CONCLUSIONS: Onvansertib combined with FOLIFRI/bevacizumab exhibited manageable safety and promising efficacy in second-line treatment of patients with KRAS-mutant metastatic colorectal cancer. Further exploration of this combination therapy is ongoing. See related commentary by Stebbing and Bullock, p. 2005.

A comprehensive study on the effect of hybridization and stacking sequence in fabricating cotton-blended jute and pineapple leaf fibre biocomposites.

Developing biocomposites by hybridization, which is the combination of two or more materials, can be a potential solution for improving material recyclability and sustainability. This study focuses on creating a hybrid biocomposite reinforced with cotton-blended pineapple leaf fibre (PALF) fabric (174 GSM) and jute fibre fabric (265 GSM) which are thrown away by textile factories. The mechanical, moisture absorption, and vibration characteristics of four stacking sequences of hybrid composites and two unhybridized composites were analyzed. Results indicated that hybridization improved tensile and flexural characteristics compared to pineapple leaf fibre reinforced polymer (PFRP) composites. The jute fibre reinforced polymer (JFRP) composite exhibited the maximum tensile strength of 35.16 MPa, while the hybrid composites achieved a maximum of 32.16 MPa. Among the hybrid composites, jute layers on the outer plies (4P5J-2) demonstrated the maximum tensile modulus of 1.315 GPa. Additionally, the hybrid composite with three layers of jute plies between alternating layers of jute-pineapple plies showed the highest elongation at 15.94%. Among the hybrids, alternate stacking of jute/PALF plies (4P5J-1) gave a maximum flexural strength of 44.36 MPa, which is similar to JFRP (44.91 MPa) and a 78.57% increase in flexural modulus compared to PFRP composite, despite having the lowest tensile strength. Although the JFRP composite exhibited the highest impact strength, the hybrids still outperformed the PFRP composites. With hybridization, moisture absorption decreased, with a maximum of 29.50% compared to the JFRP composite. Furthermore, due to the spiral-like orientation of the yarns, stacking PALF plies on the outside can cause critical damping. Therefore, it is shown in this paper that both hybridization and stacking sequence can significantly influence composite performance. These findings also implies the utilization of textile industry's natural fibres to develop hybrid composites for automotive applications, like brake and accelerator pedals, for a greener future and effective waste material utilization.

Evaluation of Intratumoral Response Heterogeneity in Metastatic Colorectal Cancer and Its Impact on Patient Overall Survival: Findings from 10,551 Patients in the ARCAD Database.

Metastatic colorectal cancer (mCRC) is a heterogeneous disease that can evoke discordant responses to therapy among different lesions in individual patients. The Response Evaluation Criteria in Solid Tumors (RECIST) criteria do not take into consideration response heterogeneity. We explored and developed lesion-based measurement response criteria to evaluate their prognostic effect on overall survival (OS). PATIENTS AND METHODS: Patients enrolled in 17 first-line clinical trials, who had mCRC with ≥ 2 lesions at baseline, and a restaging scan by 12 weeks were included. For each patient, lesions were categorized as a progressing lesion (PL: > 20% increase in the longest diameter (LD)), responding lesion (RL: > 30% decrease in LD), or stable lesion (SL: neither PL nor RL) based on the 12-week scan. Lesion-based response criteria were defined for each patient as follows: PL only, SL only, RL only, and varied responses (mixture of RL, SL, and PL). Lesion-based response criteria and OS were correlated using stratified multivariable Cox models. The concordance between OS and classifications was measured using the C statistic. RESULTS: Among 10,551 patients with mCRC from 17 first-line studies, varied responses were noted in 51.6% of patients, among whom, 3.3% had RL/PL at 12 weeks. Among patients with RL/SL, 52% had stable disease (SD) by RECIST 1.1, and they had a longer OS (median OS (mOS) = 19.9 months) than those with SL only (mOS = 16.8 months, HR (95% CI) = 0.81 (0.76, 0.85), p < 0.001), although a shorter OS than those with RL only (mOS = 25.8 months, HR (95% CI) = 1.42 (1.32, 1.53), p < 0.001). Among patients with SL/PL, 74% had SD by RECIST 1.1, and they had a longer OS (mOS = 9.0 months) than those with PL only (mOS = 8.0 months, HR (95% CI) = 0.75 (0.57, 0.98), p = 0.040), yet a shorter OS than those with SL only (mOS = 16.8 months, HR (95% CI) = 1.98 (1.80, 2.18), p < 0.001). These associations were consistent across treatment regimen subgroups. The lesion-based response criteria showed slightly higher concordance than RECIST 1.1, although it was not statistically significant. CONCLUSION: Varied responses at first restaging are common among patients receiving first-line therapy for mCRC. Our lesion-based measurement criteria allowed for better mortality discrimination, which could potentially be informative for treatment decision-making and influence patient outcomes.

Stroke services in MENA: What is there and what is needed.

OBJECTIVES: Stroke represents a health care challenge to most parts of the world including the Middle East and North Africa (MENA) region. The MENA represents 6% of the world population with an age-standardized stroke rate of 87.7 (78.2-97.6) per 100,000 population. This number is subject to increase given that the cause of morbidity has recently shifted from infectious diseases to non-communicable diseases. Thus, in the coming years, treatment of stroke will pose a major burden on MENA countries which mostly lie in the low to middle income economies. Accordingly, we need to study the state of MENA stroke services in order to recognize and further inform policy makers about any gaps that need to be bridged in this domain. METHODS AND RESULTS: Stroke specialists representing 16 countries filled an online survey that included: screening for risk factors, acute management, diagnostics, medications, post-discharge services, and stroke registries. Results showed that 11 countries screen for risk factors, 16 have neuroimaging studies, 15 provide intravenous thrombolysis (IVT), 13 mechanical thrombectomy (MT) while medications for secondary prevention are available in all countries. However, stroke units are not equally available and even absent in 4 countries, and despite the availability of IVT yet, the rate of administration is still low in 6 countries (<5%), and ranges from 5-20% in 7 countries. Stroke registries and training still need to be implemented in most countries. CONCLUSION: Although imaging, revascularization therapies and medications for secondary prevention are available in most MENA countries, yet the rate of revascularization is low, so is the number of stroke units insufficient in some countries. Additionally, registries and structured training are still defective. Further field studies are required for more accurate determination of the status of stroke services in the MENA region.

Understanding capacity fade in organic redox-flow batteries by combining spectroscopy with statistical inference techniques.

Organic redox-active molecules are attractive as redox-flow battery (RFB) reactants because of their low anticipated costs and widely tunable properties. Unfortunately, many lab-scale flow cells experience rapid material degradation (from chemical and electrochemical decay mechanisms) and capacity fade during cycling (>0.1%/day) hindering their commercial deployment. In this work, we combine ultraviolet-visible spectrophotometry and statistical inference techniques to elucidate the Michael attack decay mechanism for 4,5-dihydroxy-1,3-benzenedisulfonic acid (BQDS), a once-promising positive electrolyte reactant for aqueous organic redox-flow batteries. We use Bayesian inference and multivariate curve resolution on the spectroscopic data to derive uncertainty-quantified reaction orders and rates for Michael attack, estimate the spectra of intermediate species and establish a quantitative connection between molecular decay and capacity fade. Our work illustrates the promise of using statistical inference to elucidate chemical and electrochemical mechanisms of capacity fade in organic redox-flow battery together with uncertainty quantification, in flow cell-based electrochemical systems.

Randomized Phase II Trial Comparing Bevacizumab Plus Carboplatin and Paclitaxel With Carboplatin and Paclitaxel Alone in Previously Untreated Locally Advanced or Metastatic Non-Small-Cell Lung Cancer.

PURPOSE: To investigate the efficacy and safety of bevacizumab plus carboplatin and paclitaxel in patients with advanced or recurrent non-small-cell lung cancer. PATIENTS AND METHODS: In a phase II trial, 99 patients were randomly assigned to bevacizumab 7.5 (n = 32) or 15 mg/kg (n = 35) plus carboplatin (area under the curve = 6) and paclitaxel (200 mg/m2) every 3 weeks or carboplatin and paclitaxel alone (n = 32). Primary efficacy end points were time to disease progression and best confirmed response rate. On disease progression, patients in the control arm had the option to receive single-agent bevacizumab 15 mg/kg every 3 weeks. RESULTS: Compared with the control arm, treatment with carboplatin and paclitaxel plus bevacizumab (15 mg/kg) resulted in a higher response rate (31.5% v 18.8%), longer median time to progression (7.4 v 4.2 months) and a modest increase in survival (17.7 v 14.9 months). Of the 19 control patients that crossed over to single-agent bevacizumab, five experienced stable disease, and 1-year survival was 47%. Bleeding was the most prominent adverse event and was manifested in two distinct clinical patterns; minor mucocutaneous hemorrhage and major hemoptysis. Major hemoptysis was associated with squamous cell histology, tumor necrosis and cavitation, and disease location close to major blood vessels. CONCLUSION: Bevacizumab in combination with carboplatin and paclitaxel improved overall response and time to progression in patients with advanced or recurrent non-small-cell lung cancer. Patients with nonsquamous cell histology appear to be a subpopulation with improved outcome and acceptable safety risks.

Treatment with decitabine induces the expression of stemness markers, PD-L1 and NY-ESO-1 in colorectal cancer: potential for combined chemoimmunotherapy.

BACKGROUND: The mechanism of tumor immune escape and progression in colorectal cancer (CRC) is widely investigated in-vitro to help understand and identify agents that might play a crucial role in response to treatment and improve the overall survival of CRC patients. Several mechanisms of immune escape and tumor progression, including expression of stemness markers, inactivation of immunoregulatory genes by methylation, and epigenetic silencing, have been reported in CRC, indicating the potential of demethylating agents as anti-cancer drugs. Of these, a chemotherapeutic demethylating agent, Decitabine (DAC), has been reported to induce a dual effect on both DNA demethylation and histone changes leading to an increased expression of target biomarkers, thus making it an attractive anti-tumorigenic drug. METHODS: We compared the effect of DAC in primary 1076 Col and metastatic 1872 Col cell lines isolated and generated from patients' tumor tissues. Both cell lines were treated with DAC, and the expression of the NY-ESO-1 cancer-testis antigen, the PD-L1 immunoinhibitory marker, and the CD44, Nanog, KLF-4, CD133, MSI-1 stemness markers were analyzed using different molecular and immunological assays. RESULTS: DAC treatment significantly upregulated stemness markers in both primary 1076 Col and meta-static 1872 Col cell lines, although a lower effect occurred on the latter: CD44 (7.85 fold; ***p = 0.0001 vs. (4.19 fold; *p = 0.0120), Nanog (4.1 fold; ***p < 0.0001 vs.1.69 fold; ***p = 0.0008), KLF-4 (4.33 fold; ***p < 0.0001 vs.2.48 fold; ***p = 0.0005), CD133 (16.77 fold; ***p = 0.0003 vs.6.36 fold; *p = 0.0166), and MSI-1 (2.33 fold; ***p = 0.0003 vs.2.3 fold; ***p = 0.0004), respectively. Interestingly, in the metastatic 1872 Col cells treated with DAC, the expression of both PD-L1 and NY-ESO-1 was increased tenfold (*p = 0.0128) and fivefold (***p < 0.0001), respectively. CONCLUSIONS: We conclude that the upregulation of both stemness and immune checkpoint markers by DAC treatment on CRC cells might represent a mechanism of immune evasion. In addition, induction of NY-ESO-1 may represent an immuno-therapeutic option in metastatic CRC patients. Finally, the combination of DAC and anti-PD-1/anti-PD-L1 antibodies treatment should represent a potential therapeutic intervention for this group of patients.

Studies on anti-colon cancer potential of nanoformulations of curcumin and succinylated curcumin in mannosylated chitosan.

Colon cancer (CRC) is the second leading cause of death and the third most diagnosed cancer worldwide. Although curcumin (CUR) has demonstrated a potent anticancer activity, it is characterized by its poor solubility, low bioavailability, and instability. This study is a projection from a previous investigation where CUR and succinylated CUR (CUR.SA) were separately encapsulated in mannosylated-chitosan nanoparticles (CM-NPs) to form CUR-NPs and CUR.SA-NPs, respectively. Here, we aim to assess the anti-CRC activity of these two nanoformulations. Cytotoxicity studies using CCK-8 assay indicated that both CUR-NPs and CUR.SA-NPs have a dose and time-dependent toxicity towards CRC human cell-lines (HCT116 and SW480), and more cytotoxic compared to free CUR or CUR-SA in a time-dependent manner. A significant induction of early and late apoptosis in the CUR-NPs and CUR.SA-NPs treated CRC cell lines compared to untreated cells was observed. Western blotting analyses confirmed the induction of apoptosis through activation of Caspase signaling compared to untreated cells. Based on the physicochemical properties of CUR-NPs and CUR.SA-NPs along with the data from the in vitro studies, we may conclude these nanoparticle formulations hold very promising attributes, worthy of further investigations for its role in the management of CRC.

Expert opinion on the pharmacological management of multiple sclerosis in women of childbearing age in Iraq.

Background: Multiple sclerosis (MS) is often diagnosed in women of childbearing age (WCBA), with a mean age of onset of 30 years. Women with MS have long been cautioned to carefully plan their pregnancies and, traditionally, disease-modifying therapies (DMTs) have not been recommended for use in patients engaged in family planning. In 2020, the United States Food and Drug Administration (FDA) approved a label update for interferon beta (IFN ß) by adding new safety data on pregnancy and breastfeeding. Because current management guidelines do not yet reflect the recent label update, a panel of neurology experts from Iraq decided to discuss the potential need for changes in treatment strategies in Iraq. Methods: A panel of experts consisting of 8 neurologists from Iraq and one international neurology expert from Germany convened to develop an expert opinion that would provide practical guidance for the pharmacological management of WCBA with MS in Iraq. They considered the latest label update and relevant published literature, along with local clinical practice and available resources. Results: Interferon and Glatiramer acetate have no evidence of harm during pregnancy. IFN ß can be continued safely through pregnancy. Switching treatment during pregnancy is generally not recommended. Short-term intravenous methylprednisolone can be used to treat disabling relapses. Conclusion: Given the complexity of managing MS in pregnant women, it is the opinion of the expert panel that family planning should be discussed early in the disease course, planned pregnancy should be encouraged, and open communication with patient for her treatment decisions is paramount. Patients who are engaged in family planning are no longer discouraged from treatment with some of the currently available DMTs.

Persistence of spike-specific immune responses in BNT162b2-vaccinated donors and generation of rapid ex-vivo T cells expansion protocol for adoptive immunotherapy: A pilot study.

Introduction: The BNT162b2 mRNA-based vaccine has shown high efficacy in preventing COVID-19 infection but there are limited data on the types and persistence of the humoral and T cell responses to such a vaccine. Methods: Here, we dissect the vaccine-induced humoral and cellular responses in a cohort of six healthy recipients of two doses of this vaccine. Results and discussion: Overall, there was heterogeneity in the spike-specific humoral and cellular responses among vaccinated individuals. Interestingly, we demonstrated that anti-spike antibody levels detected by a novel simple automated assay (Jess) were strongly correlated (r=0.863, P<0.0001) with neutralizing activity; thus, providing a potential surrogate for neutralizing cell-based assays. The spike-specific T cell response was measured with a newly modified T-spot assay in which the high-homology peptide-sequences cross-reactive with other coronaviruses were removed. This response was induced in 4/6 participants after the first dose, and all six participants after the second dose, and remained detectable in 4/6 participants five months post-vaccination. We have also shown for the first time, that BNT162b2 vaccine enhanced T cell responses also against known human common viruses. In addition, we demonstrated the efficacy of a rapid ex-vivo T cell expansion protocol for spike-specific T cell expansion to be potentially used for adoptive-cell therapy in severe COVID-19, immunocompromised individuals, and other high-risk groups. There was a 9 to 13.7-fold increase in the number of expanded T cells with a significant increase of anti-spike specific response showing higher frequencies of both activation and cytotoxic markers. Interestingly, effector memory T cells were dominant in all four participants' CD8+ expanded memory T cells; CD4+ T cells were dominated by effector memory in 2/4 participants and by central memory in the remaining two participants. Moreover, we found that high frequencies of CD4+ terminally differentiated memory T cells were associated with a greater reduction of spike-specific activated CD4+ T cells. Finally, we showed that participants who had a CD4+ central memory T cell dominance expressed a high CD69 activation marker in the CD4+ activated T cells.

Characterization and adsorption of malachite green dye from aqueous solution onto Salix alba L. (Willow tree) leaves powder and its respective biochar.

In the present study, the use of low-cost, highly efficient, eco-friendly, and abundantly available (in Kashmir region, J&K India) willow leaves from which adsorbents like willow leaves powder (WLP) and willow leaves biochar (WLB) were prepared, have been found to be efficient for malachite green (MG) dye removal and can be used as an alternative to the current expensive methods of removing the same dye from an aqueous solution. The techniques like Fourier transform infrared spectroscopy (FTIR), scanning electron microscope (SEM), and carbon, hydrogen, nitrogen, sulphur (CHNS) analyser were used to characterize the samples without any chemical treatment. SEM of the adsorbents shows the presence of different sized pores, cracks, and crevices. FTIR and CHNS show functional groups and elemental concentration, respectively. The effects of various experimental parameters such as contact time, adsorbent dosage, initial dye concentration, salt treatment, and pH were investigated and optimal experimental conditions were obtained. It has been found that Langmuir, Freundlich, and Temkin isotherms were useful for describing the equilibrium of adsorption system. The equilibrium adsorption data in this research work was found to follow both Langmuir and Freundlich isotherm models and maximum monolayer capacity of WLP and WLB were found to be 10.014 and 21.244 mg/g, respectively. The experimental data for both WLP and WLB followed pseudo-second-order kinetic model with R2= 0.999. Intraparticle diffusion model reveals that more than one mechanism influenced the adsorption process. Thermodynamic study concluded that the adsorption is spontaneous for both adsorbents but exothermic for WLP and is endothermic in nature for WLB. Present exploration and comparison with other reported adsorbents concluded that, WLP and WLB may be useful as low-cost attractive option for the removal of MG dye from aqueous solution and therefore, also from wastewater containing MG dye.

This study reports for the first time the use of Salix alba L. (Willow tree) leaves and its biochar as the adsorbents for the removal of malachite green dye from its aqueous solution.Both the adsorbents namely willow leaves powder (WLP) and willow leaves biochar (WLB) are rapid and highly efficient for MG dye removal having percentage removal more than 92.5%.For WLB adsorbent the percentage removal crosses 98.5% by the addition of 0.2 g KCl and by increasing 40 °C temperatures.The adsorbents used in this research work are comparable with the highly efficient low-cost adsorbents used for MG dye like rice husk, water hyacinth, seaweed, etc. found in the literature.The adsorbents (WLP and WLB) were used without chemical treatment having good removal efficiency, cheap, easy available, and their mode of preparation is simple.

Evaluating sex as a predictive marker for response to bevacizumab in metastatic colorectal carcinoma: Pooled analysis of 3,369 patients in the ARCAD database.

BACKGROUND: Previous studies suggest a possible sex-specific response to bevacizumab in metastatic colorectal carcinoma (mCRC), showing a benefit in males, while the effect in females is less significant. METHODS: Data from 3369 patients with mCRC enrolled on four first-line randomised trials testing chemotherapy with or without bevacizumab (2000-2007) were pooled. Association between sex and progression-free survival and overall survival (OS) was evaluated by stratified Cox regression model, adjusted for potential confounders. Predictive value was evaluated by interaction effect between sex and treatment. In a pre-planned secondary analysis, analyses were stratified using an age cut point of 60 years to evaluate the possible role of menopausal-related effects. RESULTS: Bevacizumab was associated with an improved median OS in males and females, with a 2.3- and 0.6-months benefit, respectively. Stratified by age, bevacizumab resulted in improved OS in males at both age categories. In females at or above the age of 60 (n = 731), bevacizumab resulted in improved OS. However, in females below the age of 60 (n = 634), OS benefit did not reach statistical significance (adjusted hazard ratio = 0.94, 95% confidence interval 0.74-1.20). CONCLUSIONS: Our results confirmed the OS benefit from the addition of bevacizumab to first-line chemotherapy in mCRC in both sexes. Among females, the benefit was less than 1 month. For females under the age of 60, there was no survival benefit. These findings could be used to relieve financial toxicity or be redistributed within healthcare systems for other health-related purposes.

A novel patches-selection method for the classification of point-of-care biosensing lateral flow assays with cardiac biomarkers.

Cardiovascular Disease (CVD) is amongst the leading cause of death globally, which calls for rapid detection and treatment. Biosensing devices are used for the diagnosis of cardiovascular disease at the point-of-care (POC), with lateral flow assays (LFAs) being particularly useful. However, due to their low sensitivity, most LFAs have been shown to have difficulties detecting low analytic concentrations. Breakthroughs in artificial intelligence (AI) and image processing reduced this detection constraint and improved disease diagnosis. This paper presents a novel patches-selection approach for generating LFA images from the test line and control line of LFA images, analyzing the image features, and utilizing them to reliably predict and classify LFA images by deploying classification algorithms, specifically Convolutional Neural Networks (CNNs). The generated images were supplied as input data to the CNN model, a strong model for extracting crucial information from images, to classify the target images and provide risk stratification levels to medical professionals. With this approach, the classification model produced about 98% accuracy, and as per the literature review, this approach has not been investigated previously. These promising results show the proposed method may be useful for identifying a wide variety of diseases and conditions, including cardiovascular problems.

Challenges Associated with Effective Implementation of CT Dose Check Standards and Radiation Monitoring Index in Computed Tomography: Healthcare Sector Experience.

Computed tomography (CT) radiation dose management tools should be used whenever possible, particularly with the increasing demand for acquiring CT studies. Herein, we aim to assess the advantages and challenges faced with implementing two CT dose management tools. A second aim was to highlight CT examinations exceeding dose notification values (NVs) and define the common set of causes. A total of 13,037 CT examinations collected over a six-month period, were evaluated, using two independent CT dose management tools, a CT Dose Notification prospective-view tool (PVT) following CT Dose Check standards and a retrospective statistical-based view tool (RSVT). Dose NVs were set to twice the Local Diagnostic Reference Levels. There was a significant discrepancy between dose NV counts registered with prospective (4.15%) and retrospective (7.98%) tools using T-Test. A core difference is the dose configuration setup, with PVT and RSVT being dose per series and whole study, respectively. Both prospective and retrospective dose management tools were equally useful despite their technical difference. Configuring the CT prospective dose notification check tool using NVs that is based on DRLs has limitations, and one needs to establish dose NVs per series to overcome this technical hurdle. Technical challenges make the implementation of CT Dose Check standards puzzling.

Trajectories of body weight change and survival among patients with mCRC treated with systemic therapy: Pooled analysis from the ARCAD database.

BACKGROUND: Higher body mass index is associated with a higher incidence of colorectal cancer (CRC) but also with improved survival in metastatic CRC (mCRC). Whether weight change after mCRC diagnosis is associated with survival remains largely unknown. METHODS: We analysed individual patient data for previously untreated patients enrolled in five phase 3 randomised trials conducted between 1998 and 2006. Weight measurements were prospectively collected at baseline and up to 59.4 months after diagnosis. We used stratified multivariable Cox models to assess the prognostic associations of weight loss with overall and progression-free survival, adjusting for other factors. The primary end-point was a difference in overall survival (OS) between populations with weight loss and stable or increasing weight. FINDINGS: Data were available for 3504 patients. The median weight change at 3 months was -0.54% (IQR -3.9 … +1.5%). We identified a linear trend of increasing risk of death associated with progressive weight loss. Unstratified median OS was 20.5, 18.0, and 11.9 months (p < 0.001) for stable weight or gain, <5% weight loss, and ≥5% weight loss at 3 months, respectively. Weight loss was associated with a higher risk of death (<5% loss: aHR 1.18 [1.06-1.30], p < 0.002; ≥5% loss: aHR 1.87 [1.67-2.1], p < 0.001) as compared to stable or increasing weight at 3 months post-baseline (reference), while adjusting for age, sex, performance, and a number of metastatic sites. INTERPRETATION: Patients losing weight during systemic therapy for metastatic colorectal cancer have significantly shorter OS. The degree of weight loss is proportional to the observed increased risk of death and remains evident among underweight, normal weight, and obese individuals. On-treatment weight change could be used as an intermediate end-point. FUNDING: The creation and management of the database containing the individual patient data from the original randomised trials is supported by the Aide et Recherche en Cancérologie Digestive Foundation.

Toward the Identification of Natural Antiviral Drug Candidates against Merkel Cell Polyomavirus: Computational Drug Design Approaches.

Merkel cell carcinoma (MCC) is a rare form of aggressive skin cancer mainly caused by Merkel cell polyomavirus (MCPyV). Most MCC tumors express MCPyV large T (LT) antigens and play an important role in the growth-promoting activities of oncoproteins. Truncated LT promotes tumorigenicity as well as host cell proliferation by activating the viral replication machinery, and inhibition of this protein in humans drastically lowers cellular growth linked to the corresponding cancer. Our study was designed with the aim of identifying small molecular-like natural antiviral candidates that are able to inhibit the proliferation of malignant tumors, especially those that are aggressive, by blocking the activity of viral LT protein. To identify potential compounds against the target protein, a computational drug design including molecular docking, ADME (absorption, distribution, metabolism, and excretion), toxicity, molecular dynamics (MD) simulation, and molecular mechanics generalized Born surface area (MM-GBSA) approaches were applied in this study. Initially, a total of 2190 phytochemicals isolated from 104 medicinal plants were screened using the molecular docking simulation method, resulting in the identification of the top five compounds having the highest binding energy, ranging between -6.5 and -7.6 kcal/mol. The effectiveness and safety of the selected compounds were evaluated based on ADME and toxicity features. A 250 ns MD simulation confirmed the stability of the selected compounds bind to the active site (AS) of the target protein. Additionally, MM-GBSA analysis was used to determine the high values of binding free energy (ΔG bind) of the compounds binding to the target protein. The five compounds identified by computational approaches, Paulownin (CID: 3084131), Actaealactone (CID: 11537736), Epigallocatechin 3-O-cinnamate (CID: 21629801), Cirsilineol (CID: 162464), and Lycoricidine (CID: 73065), can be used in therapy as lead compounds to combat MCPyV-related cancer. However, further wet laboratory investigations are required to evaluate the activity of the drugs against the virus.