Assessment of the effectiveness of the use of tumoroids for personalized drug therapies for solid tumors

The approach to the management of cancerous neoplasms, which aims to define the effective curative strategies in each patient, defines the requirement for the elaboration and use of modelling systems that replicate the structures and the biology of human solitary tumors. Three-dimensional cultures of spheroids/tumoroids, which are multi-cell aggregates of malignized cells, can create the intercellular connections of interest, gradients of the nutrients and oxygen, and cell polarity, all of which are absent in the conventional two-dimensional single-layer system. The present work is dedicated to a comparison study of in vitro viability and invasiveness of solid tumor cells of patients under the effect of chemopreparations and their combinations in view of evaluating the efficacy of the 3D-cell modelling system in the translational personalized medicine context. Cell cultures of patients who were treated at the N.N. Petrov National Medicine Research Center of oncology were used as a basis for the development of 3D-cell models. N.N. Petrov NMRC in 2015-2021. Tumor tissue pieces were acquired intraoperatively: 1 - leiomyosarcoma (LMS), 1 - rhabdomyosarcoma (RMS), 1 - synovial sarcoma (SS), 2 - myxofibrosarcoma (MFS), 2 - osteogenic sarcoma (OS), 1 - skin melanoma (MC), 1 - breast cancer (BC) (n=9). Our individual comparison of the effectiveness of in vitro chemotherapeutic agents against tumor cells of various origins cultivated in 2D and 3D model systems with real clinically relevant cases confirmed that the monolayer culture as the test system was less adequate for selecting and personalizing the treatment of malignant tumor patients: the 3D cell system proved itself in 77.7% of cases, and the monolayer culture - in 44.4% of cases. The combination of doxorubicin/iforsfamide and paclitaxel significantly suppressed the motility in the matrigel of spheroid cells, but did not affect tumor cell viability, which was seen in all but OS #921 and MK #929 cases. The cultivation of tumor cells in form of spheroids/tumoroids allows to utilize them as more adequate pre-clinical model as individual predictive test-system, enabling the personalized selection of therapy.

Practical Consensus Recommendations for Optimizing Risk versus Benefit of Chemotherapy in Patients with HR Positive Her2 Negative Early Breast Cancer in India

Breast cancer is a public health challenge globally as well as in India. Improving outcome and cure requires appropriate biomarker testing to assign risk and plan treatment. Because it is documented that significant ethnic and geographical variations in biological and genetic features exist worldwide, such biomarkers need to be validated and approved by authorities in the region where these are intended to be used. The use of western guidelines, appropriate for the Caucasian population, can lead to inappropriate overtreatment or undertreatment in Asia and India. A virtual meeting of domain experts discussed the published literature, real-world practical experience, and results of opinion poll involving 185 oncologists treating breast cancer across 58 cities of India. They arrived at a practical consensus recommendation statement to guide community oncologists in the management of hormone positive (HR-positive) Her2-negative early breast cancer (EBC). India has a majority (about 50%) of breast cancer patients who are diagnosed in the premenopausal stage (less than 50 years of age). The only currently available predictive test for HR-positive Her2-negative EBC that has been validated in Indian patients is CanAssist Breast. If this test gives a score indicative of low risk (< 15.5), adjuvant chemotherapy will not increase the chance of metastasis-free survival and should not be given. This is applicable even during the ongoing COVID-19 pandemic.

A Multi-mRNA Prognostic Signature for Anti-TNFα Therapy Response in Patients with Inflammatory Bowel Disease

Background: Anti-TNF-alpha (anti-TNFα) therapies have transformed the care and management of inflammatory bowel disease (IBD). However, they are expensive and ineffective in greater than 50% of patients, and they increase the risk of infections, liver issues, arthritis, and lymphoma. With 1.6 million Americans suffering from IBD and global prevalence on the rise, there is a critical unmet need in the use of anti-TNFα therapies: a test for the likelihood of therapy response. Here, as a proof-of-concept, we present a multi-mRNA signature for predicting response to anti-TNFα treatment to improve the efficacy and cost-to-benefit ratio of these biologics. Methods: We surveyed public data repositories and curated four transcriptomic datasets (n = 136) from colonic and ileal mucosal biopsies of IBD patients (pretreatment) who were subjected to anti-TNFα therapy and subsequently adjudicated for response. We applied a multicohort analysis with a leave-one-study-out (LOSO) approach, MetaIntegrator, to identify significant differentially expressed (DE) genes between responders and non-responders and then used a greedy forward search to identify a parsimonious gene signature. We then calculated an anti-TNFα response (ATR) score based on this parsimonious gene signature to predict responder status and assessed discriminatory performance via an area-under-receiver operating-characteristic curve (AUROC). Results: We identified 324 significant DE genes between responders and non-responders. The greedy forward search yielded seven genes that robustly distinguish anti-TNFα responders from non-responders, with an AUROC of 0.88 (95% CI: 0.70–1). The Youden index yielded a mean sensitivity of 91%, mean specificity of 76%, and mean accuracy of 86%. Conclusions: Our findings suggest that there is a robust transcriptomic signature for predicting anti-TNFα response in mucosal biopsies from IBD patients prior to treatment initiation. This seven-gene signature should be further investigated for its potential to be translated into a predictive test for clinical use.

A Predictive Test of Outflow Enhancement by Ab Interno Trabeculectomy

Purpose: To investigate trabeculopuncture (TP) for predicting the outcome of ab interno trabeculectomy (AIT). AIT is an effective, low-risk procedure for open angle glaucoma. Despite widespread utilization, it fails in patients with an unidentified distal outflow resistance. Methods: We bisected 81 enucleated porcine eyes and perfused them for 72 hours. They were assigned to two groups: trial (n=42) and control (n=39). Intraocular pressure (IOP) was measured continuously. At 24 hours, four YAG-laser trabeculopunctures on the nasal trabecular meshwork were performed, followed by a 180&deg; AIT at the same site at 48 hours. Eyes were divided into TP and AIT responders and non-responders; the proportion of TP responders between both AIT groups was compared. Results: Both post-TP and post-AIT IOPs were lower than baseline IOP (p=0.015 and p&lt;0.01, respectively). The success rates of TP and AIT were 69% and 85.7%, respectively. The proportion of TP responders among AIT responders was greater than that of AIT non-responders (p&lt;0.01). Sensitivity and specificity values of TP as predictive test for AIT success were 77.7% and 83.3%, respectively. The positive and negative predictive values were 96.6% and 38.5%, respectively. Conclusion: A 10% reduction in IOP after TP can be used as predictor for the success (&gt;20% IOP decrease) of 180&deg; AIT in porcine eyes.

Minireview: Utilidad de las pruebas predictivas para parto pretérmino utilizadas en la práctica clínica

Preterm labor, defined as delivery before 37 weeks of gestation, is a serious obstetric condition that accounts for 11% of pregnancies worldwide. Predictive tests for preterm birth are important, given the personal, economic, and health impact of preterm birth. This review explores the utility of both, the current predictive tests used in clinical practice (maternal characteristics, cervical length and biochemical markers), as well as the new emerging tests. An electronic search was carried out in the scientific health databases: PUBMED, COCHRANE, SCIELO, national universities virtual repositories were also reviewed, using the following search items and their combinations: preterm delivery, cervical length, cervical shortening, cervicometry, fetal fibronectin, risk factors, and maternal characteristics. We included papers in English and Spanish published from 2006 to 2020, which responded to the aim of the review: the utility of predictive test for preterm delivery. A total of 30 articles were included in this review. There are multiple scientific criteria on the different current techniques to identify patients at risk and achieve adequate prevention of preterm birth. Measurement of cervical length by transvaginal ultrasound is the most cost-effective method in women with a history of preterm labor or symptoms of preterm labor; the current evidence allows us to affirm that it is also essential to perform routine cervicometry in all patients, even with low risk. There are promising ultrasound predictive methods such as cervical elastography and cervical consistency index, but there are limitations in their technical implementation, it is proposed that they could be a possible alternative in the future, that can be combined with cervical length measurement. Also, adding cervical length easurement to biochemical tests appears to improve predictive accuracy.

Medial Prefrontal Cortex controlling the immobility of rats in the forced swimming test: a systematic review and meta-analysis

The medial prefrontal cortex (mPFC) belong to the neural circuitry responsible for the behavioral responses to antidepressants in humans or animals. In the forced swimming (FST), a predictive test for antidepressants in laboratory rodents, inhibition, or stimulation of mPFC may produce antidepressant-like, unlike or no behavioral effect at all. Controversial findings may result from the variety of subregions of mPFC controlling behaviour of rats in the FST. The aim in the present study was to estimate the contribution of subregions of the mPFC to the control of rat behavior in the FST. For an unbiased view and well-powered analysis of the mentioned effects, a systematic review at Medline (Pubmed) followed by a meta-analysis was performed. Compared to other subdivisions, inhibition of prelimbic or infralimbic mPFC caused a significant drop of immobility time in the FST, which is an antidepressant-like effect. Summarizing, prelimbic or infralimbic cortices seem more relevant than other subregions to the control of immobility in the FST underlying the effects of antidepressants on mood and behaviour.

PREDICTION OF PREECLAMPSIA BY UTERINE ARTERY DOPPLER VELOCIMETRY BETWEEN 16-28 WEEKS

Background: Preeclampsia is a multisystem disorder which affects about 2% of pregnancies and represents a major threat to mother and foetus when it emerges. In some women this condition sets in a subtle way and gradually such women develop severe degree of preeclampsia leading to dreadful complications. Uterine artery doppler velocimetry is a non-invasive method to examine the uteroplacental circulation that provides indirect evidence of blood ow and is proposed a predictive test for preeclampsia. This prospective observational study was performed to assess the usefulness of uterine artery Doppler in predicting preeclampsia. Methods: 50 high risk and 50 low risk singleton pregnancies between 16-28 weeks of gestational age with uterine artery doppler study were followed up till delivery or development of preeclampsia to determine maternal and fetal outcome. Results: Sensitivity and specicity of abnormal uterine artery doppler study for prediction of preeclampsia were 90 % and 70 % in high-risk and 42 % and 90 % in low-risk group, respectively. Positive predictive value and negative predictive value was 92 % and 63 % in high risk group and 42 % and 90 % in low risk group respectively. Conclusions: Mid trimester doppler velocimetry of uterine artery can be used as a reliable screening test for prediction of preeclampsia in both high-risk and low-risk women.

An econometric modelling of the savings – investments nexus for Ghana

Introduction. The problem under discussion is whether savings are associated with investments in the long-term and whether savings predict investment with feedback or not. Addressing the problem is important since it informs policy formulation in the financial sector in ensuring efficient financial intermediation. The purpose of the article is looks at the savings-investment relationship for Ghana during the period 1960 to 2016. Methodology. Utilizing ARDL (with bounds testing) approach, the Granger predictive test, the Generalised Impulse Response Function, and Variance decomposition function. Results. The results indicate that a 1% increase in savings, GDP and financial development would result in a 0.069%, 0.266% and 0.125% increase respectively in investment in the short-term. It is discovered that savings do not cause investment in the long-run but rather in the short-run. The Granger causality test establishes a unidirectional causality running from savings to investment in the short-run. Discussion and Conclusion. The ramifications of the finding are that there is capital fixed status globally. Future examinations ought to consider structural break(s) issues as well as panel analysis to determine if the findings of the current study would be reproduced.

A BASELINE GENE EXPRESSION-BASED PROGNOSTIC FOR ANTI-TNFα THERAPY RESPONSE IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE

Background Although anti-TNFα therapies have revolutionized the management and care of IBD, their administration and usage remain suboptimal because 1) over 50% of patients do not have a lasting therapeutic response, 2) they increase risk of infections, liver problems, arthritis, and lymphoma, and 3) they are expensive. With approximately 1.6 million people suffering from IBD in the US and global prevalence of IBD on the rise, a predictive test for anti-TNFα response would greatly improve the efficacy and cost-to-benefit ratio of these biologics. Methods We hypothesized that a multicohort analysis of the publicly available IBD gene expression datasets would yield a robust set of mRNAs for distinguishing anti-TNFα responders vs non-responders in the IBD patient population prior to treatment. We identified 5 datasets (n = 160) where whole-genome transcriptomic data was derived from colonic mucosal biopsies of IBD patients who were then subjected to anti-TNFα therapy and subsequently adjudicated for response. We used the MetaIntegrator framework which leverages a leave-one-study-out cross-validation technique in conjunction with effect size and FDR adjusted p-value to identify significant differentially expressed (DE) genes associated with a patient’s predisposition to a response outcome. DE genes were subjected to a greedy forward search to derive a parsimonious gene signature for a response score (geometric mean of the expression level for all positive mRNAs minus the geometric mean of the expression level of all negative mRNAs, multiplied by the ratio of counts of positive to negative genes). Area under the receiver operating characteristic curve (AUC) was subsequently calculated in a leave-one-study-out manner to assess discriminatory performance. Results We first identified 170 genes that were present in at least 40% of cohorts and significantly differentially expressed between responders and non-responders with effect size &gt; 0.8 and q value &lt; 0.1. A score based on these genes predicts responder vs non-responder across the 5 discovery cohorts with AUC of 0.82. Optimizing the variables with a greedy forward search algorithm allowed us to downselect to 7 genes from the set, and a score based on this parsimonious set of 7 genes improved the discriminatory performance to an AUC of 0.87. Choosing a high sensitivity (90%) for a rule-in scenario, the score had moderate specificity (60%); alternatively choosing a high specificity (90%) for a rule-out scenario, the score still had a good sensitivity (80%). Conclusions These initial findings suggest that there is a strong signal for predicting anti-TNFα response in colonic biopsies. In particular, we showed using the leave-one-study-out approach that a predictive signature using mRNA can be generalizable (works in independent cohorts). These initial results warrant further investigation.