Emerging Therapeutic Strategies to Overcome Drug Resistance in Cancer Cells.

The rise of drug resistance in cancer cells presents a formidable challenge in modern oncology, necessitating the exploration of innovative therapeutic strategies. This review investigates the latest advancements in overcoming drug resistance mechanisms employed by cancer cells, focusing on emerging therapeutic modalities. The intricate molecular insights into drug resistance, including genetic mutations, efflux pumps, altered signaling pathways, and microenvironmental influences, are discussed. Furthermore, the promising avenues offered by targeted therapies, combination treatments, immunotherapies, and precision medicine approaches are highlighted. Specifically, the synergistic effects of combining traditional cytotoxic agents with molecularly targeted inhibitors to circumvent resistance pathways are examined. Additionally, the evolving landscape of immunotherapeutic interventions, including immune checkpoint inhibitors and adoptive cell therapies, is explored in terms of bolstering anti-tumor immune responses and overcoming immune evasion mechanisms. Moreover, the significance of biomarker-driven strategies for predicting and monitoring treatment responses is underscored, thereby optimizing therapeutic outcomes. For insights into the future direction of cancer treatment paradigms, the current review focused on prevailing drug resistance challenges and improving patient outcomes, through an integrative analysis of these emerging therapeutic strategies.

Development and validation of AI-derived segmentation of four-chamber cine cardiac magnetic resonance.

BACKGROUND: Cardiac magnetic resonance (CMR) in the four-chamber plane offers comprehensive insight into the volumetrics of the heart. We aimed to develop an artificial intelligence (AI) model of time-resolved segmentation using the four-chamber cine. METHODS: A fully automated deep learning algorithm was trained using retrospective multicentre and multivendor data of 814 subjects. Validation, reproducibility, and mortality prediction were evaluated on an independent cohort of 101 subjects. RESULTS: The mean age of the validation cohort was 54 years, and 66 (65%) were males. Left and right heart parameters demonstrated strong correlations between automated and manual analysis, with a ρ of 0.91-0.98 and 0.89-0.98, respectively, with minimal bias. All AI four-chamber volumetrics in repeatability analysis demonstrated high correlation (ρ = 0.99-1.00) and no bias. Automated four-chamber analysis underestimated both left ventricular (LV) and right ventricular (RV) volumes compared to ground-truth short-axis cine analysis. Two correction factors for LV and RV four-chamber analysis were proposed based on systematic bias. After applying the correction factors, a strong correlation and minimal bias for LV volumetrics were observed. During a mean follow-up period of 6.75 years, 16 patients died. On stepwise multivariable analysis, left atrial ejection fraction demonstrated an independent association with death in both manual (hazard ratio (HR) = 0.96, p = 0.003) and AI analyses (HR = 0.96, p < 0.001). CONCLUSION: Fully automated four-chamber CMR is feasible, reproducible, and has the same real-world prognostic value as manual analysis. LV volumes by four-chamber segmentation were comparable to short-axis volumetric assessment. TRIALS REGISTRATION: ClinicalTrials.gov: NCT05114785. RELEVANCE STATEMENT: Integrating fully automated AI in CMR promises to revolutionise clinical cardiac assessment, offering efficient, accurate, and prognostically valuable insights for improved patient care and outcomes. KEY POINTS: • Four-chamber cine sequences remain one of the most informative acquisitions in CMR examination. • This deep learning-based, time-resolved, fully automated four-chamber volumetric, functional, and deformation analysis solution. • LV and RV were underestimated by four-chamber analysis compared to ground truth short-axis segmentation. • Correction bias for both LV and RV volumes by four-chamber segmentation, minimises the systematic bias.

Nanoengineering Solutions for Cancer Therapy: Bridging the Gap between Clinical Practice and Translational Research.

Nanoengineering has emerged as a progressive method in cancer treatment, offering precise and targeted delivery of therapeutic agents while concurrently reducing overall toxicity. This scholarly article delves into the innovative strategies and advancements in nanoengineering that bridge the gap between clinical practice and research in the field of cancer treatment. Various nanoengineered platforms such as nanoparticles, liposomes, and dendrimers are scrutinized for their capacity to encapsulate drugs, augment drug efficacy, and enhance pharmacokinetics. Moreover, the article investigates research breakthroughs that drive the progression and enhancement of nanoengineered remedies, encompassing the identification of biomarkers, establishment of preclinical models, and advancement of biomaterials, all of which are imperative for translating laboratory findings into practical medical interventions. Furthermore, the integration of nanotechnology with imaging modalities, which amplify cancer detection, treatment monitoring, and response assessment, is thoroughly examined. Finally, the obstacles and prospective directions in nanoengineering, including regulatory challenges and issues related to scalability, are examined. This underscores the significance of fostering collaboration among various entities in order to efficiently translate nanoengineered interventions into enhanced cancer therapies and patient management.

Pulmonary transit time is a predictor of outcomes in heart failure: a cardiovascular magnetic resonance first-pass perfusion study.

BACKGROUND: Pulmonary transit time (PTT) can be measured automatically from arterial input function (AIF) images of dual sequence first-pass perfusion imaging. PTT has been validated against invasive cardiac catheterisation correlating with both cardiac output and left ventricular filling pressure (both important prognostic markers in heart failure). We hypothesized that prolonged PTT is associated with clinical outcomes in patients with heart failure. METHODS: We recruited outpatients with a recent diagnosis of non-ischaemic heart failure with left ventricular ejection fraction (LVEF) < 50% on referral echocardiogram. Patients were followed up by a review of medical records for major adverse cardiovascular events (MACE) defined as all-cause mortality, heart failure hospitalization, ventricular arrhythmia, stroke or myocardial infarction. PTT was measured automatically from low-resolution AIF dynamic series of both the LV and RV during rest perfusion imaging, and the PTT was measured as the time (in seconds) between the centroid of the left (LV) and right ventricle (RV) indicator dilution curves. RESULTS: Patients (N = 294) were followed-up for median 2.0 years during which 37 patients (12.6%) had at least one MACE event. On univariate Cox regression analysis there was a significant association between PTT and MACE (Hazard ratio (HR) 1.16, 95% confidence interval (CI) 1.08-1.25, P = 0.0001). There was also significant association between PTT and heart failure hospitalisation (HR 1.15, 95% CI 1.02-1.29, P = 0.02) and moderate correlation between PTT and N-terminal pro B-type natriuretic peptide (NT-proBNP, r = 0.51, P < 0.001). PTT remained predictive of MACE after adjustment for clinical and imaging factors but was no longer significant once adjusted for NT-proBNP. CONCLUSIONS: PTT measured automatically during CMR perfusion imaging in patients with recent onset non-ischaemic heart failure is predictive of MACE and in particular heart failure hospitalisation. PTT derived in this way may be a non-invasive marker of haemodynamic congestion in heart failure and future studies are required to establish if prolonged PTT identifies those who may warrant closer follow-up or medicine optimisation to reduce the risk of future adverse events.

CMR characterization of patients with heart failure and left bundle branch block.

Aims: We aimed to identify the distinctive cardiovascular magnetic resonance (CMR) features of patients with left bundle branch block (LBBB) and heart failure with reduced ejection fraction (HFrEF) of presumed non-ischaemic aetiology. The secondary aim was to determine whether these individuals exhibit characteristics that could potentially serve as predictors of left ventricular ejection fraction (LVEF) recovery as compared with patients without LBBB. Methods and results: We prospectively recruited patients with HFrEF (LVEF ≤ 40%) on echocardiography who were referred for early CMR examination. Patients with an established diagnosis of coronary artery disease and known structural or congenital heart disease were excluded. LV recovery was defined as achieving ≥10% absolute improvement to ≥40% in LVEF between baseline evaluation to CMR. A total of 391 patients were recruited including 115 (29.4%) with LBBB. Compared with HF patients without LBBB, those with LBBB exhibited larger left ventricles and smaller right ventricles, but no differences were observed with respect to LVEF (35.8 ± 12 vs. 38 ± 12%, P = 0.105). The overall rate of LV recovery from baseline echocardiogram to CMR (70 [42-128] days) was not significantly different between LBBB and non-LBBB patients (27.8% vs. 31.5%, P = 0.47). Reduced LVEF remained an independent predictor of LV non-recovery only in patients with LBBB. Conclusion: Patients presenting with HFrEF and LBBB had larger LV cavities and smaller RV cavities than those without LBBB but no difference in prevalence of scar or ischaemia. The rates of LV recovery were similar between both groups, which supports current guidelines to defer device therapy until 3-6 months of guideline-directed medical therapy, rather than early CMR and device implantation.

Hindi translation and cultural adaptation of the quality of recovery score-40 (QoR-40 score): A validation study.

Background and Aims: The quality of recovery (QoR)-40 score has been used worldwide and validated in many surgical cohorts to assess global patient recovery. We aim to translate and culturally adapt the QoR-40 score into Hindi and test the validity and reliability of the translated version in patients undergoing cancer surgery. Methods: The translation of the QoR-40 questionnaire was based on the forward and backward translation methods. Patients filled out the translated version of the QoR-40 preoperatively, on the third postoperative day in the morning (POD3) and the evening. The reliability of the translated questionnaire was checked for internal consistency, test-retest reliability and split-half reliability. Construct validity was assessed with a correlation coefficient value between the total QoR-40 score, visual analogue scale (VAS) for pain and total length of hospital stay. Content validity was evaluated for feasibility and understanding. Results: The questionnaire was completed by 350 patients. The correlation coefficient r for repeatability was 0.21, the split-half test was 0.92, and Cronbach's alpha was 0.82. The correlation between QoR-40 on POD3 with VAS score and length of stay was -0.35 and -0.67, respectively. The average time to complete the questionnaire was 3.8 minutes; 90% of the respondents found the translated questionnaire easy to understand, and 92% of the patients related the questions to their recovery. Conclusion: The Hindi translation of the QoR-40 questionnaire is a valid and reliable version of the original questionnaire in English to assess the QoR in Hindi-speaking patients after cancer surgery.

Discovery of a potent, selective, and tumor-suppressing antibody antagonist of adenosine A2A receptor.

New immune checkpoints are emerging in a bid to improve response rates to immunotherapeutic drugs. The adenosine A2A receptor (A2AR) has been proposed as a target for immunotherapeutic development due to its participation in immunosuppression of the tumor microenvironment. Blockade of A2AR could restore tumor immunity and, consequently, improve patient outcomes. Here, we describe the discovery of a potent, selective, and tumor-suppressing antibody antagonist of human A2AR (hA2AR) by phage display. We constructed and screened four single-chain variable fragment (scFv) libraries-two synthetic and two immunized-against hA2AR and antagonist-stabilized hA2AR. After biopanning and ELISA screening, scFv hits were reformatted to human IgG and triaged in a series of cellular binding and functional assays to identify a lead candidate. Lead candidate TB206-001 displayed nanomolar binding of hA2AR-overexpressing HEK293 cells; cross-reactivity with mouse and cynomolgus A2AR but not human A1, A2B, or A3 receptors; functional antagonism of hA2AR in hA2AR-overexpressing HEK293 cells and peripheral blood mononuclear cells (PBMCs); and tumor-suppressing activity in colon tumor-bearing HuCD34-NCG mice. Given its therapeutic properties, TB206-001 is a good candidate for incorporation into next-generation bispecific immunotherapeutics.

Sex-specific cardiac magnetic resonance pulmonary capillary wedge pressure.

Aims: Heart failure (HF) with preserved ejection fraction disproportionately affects women. There are no validated sex-specific tools for HF diagnosis despite widely reported differences in cardiac structure. This study investigates whether sex, as assigned at birth, influences cardiac magnetic resonance (CMR) assessment of left ventricular filling pressure (LVFP), a hallmark of HF agnostic to ejection fraction. Methods and results: A derivation cohort of patients with suspected pulmonary hypertension and HF from the Sheffield centre underwent invasive right heart catheterization and CMR within 24 h of each other. A sex-specific CMR model to estimate LVFP, measured as pulmonary capillary wedge pressure (PCWP), was developed using multivariable regression. A validation cohort of patients with confirmed HF from the Leeds centre was used to evaluate for the primary endpoints of HF hospitalization and major adverse cardiovascular events (MACEs). Comparison between generic and sex-specific CMR-derived PCWP was undertaken. A total of 835 (60% female) and 454 (36% female) patients were recruited into the derivation and validation cohorts respectively. A sex-specific model incorporating left atrial volume and left ventricular mass was created. The generic CMR PCWP showed significant differences between males and females (14.7 ± 4 vs. 13 ± 3.0 mmHg, P > 0.001), not present with the sex-specific CMR PCWP (14.1 ± 3 vs. 13.8 mmHg, P = 0.3). The sex-specific, but not the generic, CMR PCWP was associated with HF hospitalization (hazard ratio 3.9, P = 0.0002) and MACE (hazard ratio 2.5, P = 0.001) over a mean follow-up period of 2.4 ± 1.2 years. Conclusion: Accounting for sex improves precision and prognostic performance of CMR biomarkers for HF.

An Innocuous-Looking Abdominal Wall Swelling in an Endometrial Cancer Survivor.

This case report describes a rare example of a solitary abdominal wall metastasis in a middle-aged endometrial cancer (EC) survivor 3 years following disease-free status. Following induction chemotherapy, she had a margin-negative surgical excision of the abdominal tumor. Surprisingly, the patient has been disease-free for more than 3 years after the operation. This emphasizes the necessity of addressing single metastasis amenable to surgical resection, as well as the need for diligent monitoring to discover recurrences sooner. Understanding rare locations of recurrence, such as the abdominal wall, is critical for optimum EC therapy and care. The data given in this article adds to the existing body of information on atypical presentations and recurrent EC therapy. Additional research is required to develop evidence-based guidance.

Emerging biomarkers and molecular targets for precision medicine in cervical cancer.

Cervical cancer remains a significant global health burden, necessitating innovative approaches for improved diagnostics and personalized treatment strategies. Precision medicine has emerged as a promising paradigm, leveraging biomarkers and molecular targets to tailor therapy to individual patients. This review explores the landscape of emerging biomarkers and molecular targets in cervical cancer, highlighting their potential implications for precision medicine. By integrating these biomarkers into comprehensive diagnostic algorithms, clinicians can identify high-risk patients at an earlier stage, enabling timely intervention and improved patient outcomes. Furthermore, the identification of specific molecular targets has paved the way for the development of targeted therapies aimed at disrupting key pathways implicated in cervical carcinogenesis. In conclusion, the evolving landscape of biomarkers and molecular targets presents exciting opportunities for advancing precision medicine in cervical cancer. By harnessing these insights, clinicians can optimize treatment selection, enhance patient outcomes, and ultimately transform the management of this devastating disease.

Should an Incidental Meckel Diverticulum Be Resected? A Systematic Review.

Background: Meckel Diverticulum [MD), a common congenital anomaly of the gastrointestinal tract, poses a dilemma when incidentally encountered during surgery. Despite historical descriptions and known complications of symptomatic MD, the decision to resect an incidental MD (IMD) lacks clear guidelines. This study aims to assess whether resecting IMDs is justified by synthesizing evidence from studies published between 2000 and 2023. Factors influencing this decision, such as demographic risks, surgical advancements and complications, are systematically examined. Methods and Material: Following the PRISMA 2020 guidelines, this review incorporates 42 eligible studies with data on outcomes of asymptomatic MD management. Studies, both favoring and opposing resection, were analyzed. Results: Considering complications, malignancy potential, and operative safety, the risk-benefit analysis presents a nuanced picture. Some authors propose conditional resection based on specific criteria, emphasizing patient-specific factors. Of 2934 cases analyzed for short- and long-term complications, the morbidity rate was 5.69%. Of 571 cases where mortality data were available, all 5 fatalities were attributed to the primary disease rather than IMD resection. Conclusion: The sporadic, unpredictable presentation of IMD and the variability of both the primary disease and the patient make formulation of definitive guidelines challenging. The non-uniformity of complications reporting underscores the need for standardized categorization. While the balance of evidence leans towards resection of IMDs, this study acknowledges the individualized nature of this decision. Increased safety in surgery and anesthesia, along with better understanding and management of complications favor a judicious preference for resection, while taking into account patient characteristics and the primary disease.

Knowledge, attitude, and practices about breast cancer among women in a high-altitude sub-Himalayan region: Are we reaching the unreached?

Background: Breast cancer awareness and early detection are critical for reducing the global burden of the disease. This study assessed breast cancer awareness among women in a high-altitude sub-Himalayan region of North India. Materials and Methods: A cross-sectional survey was conducted among women attending the gynecology outpatient clinic in a district hospital. A structured questionnaire was used to collect data on breast cancer knowledge, attitudes, and practices. Participants received posttest health education and counseling on breast cancer prevention strategies. Result: The study included 188 participants with a mean age of 31.0 ± 8.8 years. The findings revealed inadequate knowledge about breast cancer among a significant portion of the cohort. Misconceptions about risk factors, such as breastfeeding, oral contraceptive use, and past wrongdoings, were observed. Only half of the participants believed early-stage breast cancer could be effectively treated. Limited awareness of screening methods, including self-breast examination and mammography, was noted. Barriers to breast self-examination (BSE) included considering it unnecessary and lacking knowledge about its execution. Conclusion: This study highlights insufficient breast cancer awareness in the high-altitude sub-Himalayan region. Targeted interventions, including health campaigns and electronic media, should be prioritized to improve knowledge and promote early detection practices.

A systematic review of artificial intelligence tools for chronic pulmonary embolism on CT pulmonary angiography.

Background: Chronic pulmonary embolism (PE) may result in pulmonary hypertension (CTEPH). Automated CT pulmonary angiography (CTPA) interpretation using artificial intelligence (AI) tools has the potential for improving diagnostic accuracy, reducing delays to diagnosis and yielding novel information of clinical value in CTEPH. This systematic review aimed to identify and appraise existing studies presenting AI tools for CTPA in the context of chronic PE and CTEPH. Methods: MEDLINE and EMBASE databases were searched on 11 September 2023. Journal publications presenting AI tools for CTPA in patients with chronic PE or CTEPH were eligible for inclusion. Information about model design, training and testing was extracted. Study quality was assessed using compliance with the Checklist for Artificial Intelligence in Medical Imaging (CLAIM). Results: Five studies were eligible for inclusion, all of which presented deep learning AI models to evaluate PE. First study evaluated the lung parenchymal changes in chronic PE and two studies used an AI model to classify PE, with none directly assessing the pulmonary arteries. In addition, a separate study developed a CNN tool to distinguish chronic PE using 2D maximum intensity projection reconstructions. While another study assessed a novel automated approach to quantify hypoperfusion to help in the severity assessment of CTEPH. While descriptions of model design and training were reliable, descriptions of the datasets used in training and testing were more inconsistent. Conclusion: In contrast to AI tools for evaluation of acute PE, there has been limited investigation of AI-based approaches to characterising chronic PE and CTEPH on CTPA. Existing studies are limited by inconsistent reporting of the data used to train and test their models. This systematic review highlights an area of potential expansion for the field of AI in medical image interpretation.There is limited knowledge of A systematic review of artificial intelligence tools for chronic pulmonary embolism in CT. This systematic review provides an assessment on research that examined deep learning algorithms in detecting CTEPH on CTPA images, the number of studies assessing the utility of deep learning on CTPA in CTEPH was unclear and should be highlighted.