Efficacy and safety of diphereline 11.25 mg, microrelin 11.25 mg, and microrelin 3.75 mg in premenopausal patients with breast cancer: a non-inferiority randomized clinical trial.

BACKGROUND: Diphereline is a Gonadotropin-Releasing Hormone agonist commonly used in patients with breast cancer. This study aimed to compare the efficacy and safety of one-month and three-month Microrelin injections produced by Homa Pharmed Company with three-month Diphereline injections manufactured by IPSEN, France. METHODS: The study was a non-inferiority randomized clinical trial conducted between 2019 and 2023 on premenopausal women candidates for endocrine therapy. The participants were randomly assigned in blocks of six to one of three groups named A (Diphereline 11.25 mg), B (Microrelin 11.25 mg), and C (Microrelin 3.75 mg). The participants' menopausal symptoms, estradiol, and FSH serum levels were recorded in three-month intervals for one year. The efficacy of each medication and its side effects were compared among the three groups by statistical analysis during the one-year follow-up. RESULTS: The study included 133 patients with breast cancer. A decreasing trend in the serum levels of FSH and estradiol and an increasing trend of menopausal symptoms were recorded during the study. No specific side effects leading to drug disruption, hospitalization, or exclusion from the study were observed. Adjusting the effect of study group and time showed no significant changes in estradiol levels between groups B (p = 0.506) and C (p = 0.607) and group A. Also, serum FSH changes between groups B (p = 0.132) and C (p = 0.104) compared to group A were not significant. Moreover, the menopausal symptoms during the one-year follow-up did not significantly increase in group B (p = 0.108) and C (p = 0.113) compared to group A. CONCLUSIONS: It can be concluded that injections of both Microrelin 11.25 mg and 3.75 mg, produced by Homa Pharmed, Iran, are non-inferior in terms of effectiveness and incidence of menopausal symptoms compared to Diphereline, manufactured by IPSEN, France. TRIAL REGISTRATION: IRCT.ir, IRCT20201227049847N1; Registered on 09/01/2021.

A micropillar array-based microfluidic chip for label-free separation of circulating tumor cells: The best micropillar geometry?

INTRODUCTION: The information derived from the number and characteristics of circulating tumor cells (CTCs), is crucial to ensure appropriate cancer treatment monitoring. Currently, diverse microfluidic platforms have been developed for isolating CTCs from blood, but it remains a challenge to develop a low-cost, practical, and efficient strategy. OBJECTIVES: This study aimed to isolate CTCs from the blood of cancer patients via introducing a new and efficient micropillar array-based microfluidic chip (MPA-Chip), as well as providing prognostic information and monitoring the treatment efficacy in cancer patients. METHODS: We fabricated a microfluidic chip (MPA-Chip) containing arrays of micropillars with different geometries (lozenge, rectangle, circle, and triangle). We conducted numerical simulations to compare velocity and pressure profiles inside the micropillar arrays. Also, we experimentally evaluated the capture efficiency and purity of the geometries using breast and prostate cancer cell lines as well as a blood sample. Moreover, the device's performance was validated on 12 patients with breast cancer (BC) in different states. RESULTS: The lozenge geometry was selected as the most effective and optimized micropillar design for CTCs isolation, providing high capture efficiency (>85 %), purity (>90 %), and viability (97 %). Furthermore, the lozenge MPA-chip was successfully validated by the detection of CTCs from 12 breast cancer (BC) patients, with non-metastatic (median number of 6 CTCs) and metastatic (median number of 25 CTCs) diseases, showing different prognoses. Also, increasing the chemotherapy period resulted in a decrease in the number of captured CTCs from 23 to 7 for the metastatic patient. The MPA-Chip size was only 0.25 cm2 and the throughput of a single chip was 0.5 ml/h, which can be increased by multiple MPA-Chips in parallel. CONCLUSION: The lozenge MPA-Chip presented a novel micropillar geometry for on-chip CTC isolation, detection, and staining, and in the future, the possibilities can be extended to the culture of the CTCs.

Genetic variation of Amaranthus retroflexus L. and Chenopodium album L. (Amaranthaceae) suggests multiple independent introductions into Iran.

Amaranthus retroflexus L. and Chenopodium album L. (Amaranthaceae) are weedy plants that cause severe ecological and economic damage. In this study, we collected DNA from three different countries and assessed genetic diversity using inter-simple sequence repeat (ISSR) markers. Our analysis shows both weed species have low genetic diversity within a population and high genetic diversity among populations, as well as a low value of gene flow among the populations. UPGMA clustering and principal coordinate analysis indicate four distinct groups for A. retroflexus L. and C. album L. exist. We detected significant isolation-by-distance for A. retroflexus L. and no significant correlation for C.album L. These conclusions are based data from 13 ISSR primers where the average percentage of polymorphism produced was 98.46% for A. retroflexus L. and 74.81% for C. album L.These data suggest that each population was independently introduced to the location from which it was sampled and these noxious weeds come armed with considerable genetic variability giving them the opportunity to manifest myriad traits that could be used to avoid management practices. Our results, albeit not definitive about this issue, do not support the native status of C. album L. in Iran.

Redroot Pigweed (Amaranthus retroflexus L.) and Lamb's Quarters (Chenopodium album L.) Populations Exhibit a High Degree of Morphological and Biochemical Diversity.

Amaranthus retroflexus L. and Chenopodium album L. are noxious weeds that have a cosmopolitan distribution. These species successfully invade and are adapted to a wide variety of diverse climates. In this paper, we evaluated the morphology and biochemistry of 16 populations of A. retroflexus L. and 17 populations of C. album L. Seeds from populations collected from Spain, France, and Iran were grown together at the experimental field of the agriculture research of University of Mohaghegh Ardabili, and a suite of morphological traits and biochemical traits were assessed. Among the populations of A. retroflexus L. and of C. album L. were observed significant differences for all the measured traits. The number of branches (BN) for A. retroflexus L. (12.22) and inflorescence length (FL; 14.34) for C. album L. were the two characteristics that exhibited the maximum coefficient of variation. Principal component analysis of these data identified four principal components for each species that explained 83.54 (A. retroflexus L.) and 88.98 (C. album L.) of the total variation. A dendrogram based on unweighted neighbor-joining method clustered all the A. retroflexus L. and C. album L. into two main clusters and four sub-clusters. Canonical correlation analysis (CCA) was used to evaluate relationships between climate classification of origin and traits. Similarly, the measured characteristics did not group along Köppen climate classification. Both analyses support the conclusion that A. retroflexus L. and C. album L. exhibit high levels of diversity despite similar environmental histories. Both species also exhibit a high diversity of the measured biochemical compounds indicating that they exhibit different metabolic profiles even when grown concurrently and sympatrically. Several of the biochemical constituents identified in our study could serve as effective indices for indirect selection of stresses resistance/tolerance of A. retroflexus L. and C. album L. The diversity of the morphological and biochemical traits observed among these populations illustrates how the unique selection pressures faced by each population can alter the biology of these plants. This understanding provides new insights to how these invasive plant species successfully colonize diverse ecosystems and suggests methods for their management under novel and changing environmental conditions.

Heterogeneity analysis of diffusion-weighted MRI for prediction and assessment of microstructural changes early after one cycle of induction chemotherapy in nasopharyngeal cancer patients.

PURPOSE: To evaluate whether the pretreatment apparent diffusion coefficient (ADC) heterogeneity parameters and their alterations, after one cycle of induction chemotherapy, can be used as reliable markers of treatment response to induction chemotherapy in patients with nasopharyngeal cancer. MATERIALS AND METHODS: Ten patients were recruited and received induction chemotherapy (IC). Diffusion-weighted imaging was performed prior to, during, and after IC. The first-order ADC histogram parameters at the intra-treatment time-point were compared to the baseline time-point in the metastatic lymph nodes (LNs). Some ADC pretreatment parameters were combined with each other, employing discriminant analysis to achieve a feasible model to separate the complete response (CR) from the partial response (PR) groups. RESULTS: For ten patients, significant rise in Mean and Txt1Mean (p = 0.048 and 0.015, respectively) was observed in the metastatic nodes following one cycle of IC. Txt5Energy significantly decreased (p = 0.002). Discriminant analysis on pretreatment parameters illustrated that Txt5Energypre was the best parameter to use to correctly classify CR and PR patients. This was followed by Txt9Percentile75pre, Txt1Meanpre, and Txt2Standard Deviationpre. CONCLUSIONS: Our results suggest that heterogeneity metrics extracted from ADC-maps in metastatic lymph nodes, before and after IC, can be used as supplementary IC response indicators.

Food deprivation and social inequality may lead to oxidative damage: a study on the preventive role of melatonin in the male rat reproductive system.

Spermatogenic cells are susceptible to oxidative stress and apoptosis. Food deprivation (FD) has been reported as a stressor that could increase reactive oxygen species. In the present study, FD-induced oxidative stress and apoptosis, as well as the protective effects of melatonin, were evaluated in the testes. Wistar rats in the control group were fed a standard diet, whereas a sham group was administered saline as the melatonin vehicle. A third group received daily injections of melatonin (5mgkg-1 bodyweight). These rats were further divided into four groups of rats that were either subjected to FD, FD + isolation, FD + melatonin injection and FD + melatonin injection + isolation. Testicular tissues were evaluated for malondialdehyde (MDA) and reduced glutathione (GSH) concentrations, as well as and DNA damage. FD increased MDA and reduced GSH concentrations, whereas melatonin treatment improved these parameters. Immunohistochemistry for capsase-3 and terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end-labelling revealed that the number of apoptotic cells was increased in rats subjected to FD alone. Melatonin treatment offset the number of apoptotic cells following FD. The results provide evidence that FD can increase oxidative stress, leading to activation of apoptosis, and that melatonin has the ability to protect the testes against oxidative damage induced by FD.

Protective Effect of Melatonin against Inequality-Induced Da mages on Testicular Tissue and Sper m Para meters.

BACKGROUND: The goals of the study are evaluation the effects of food deprivation and isolation situation as a social stress on fertility; and in the following, investigation of the improving effect of melatonin as an antioxidant component. MATERIALS AND METHODS: In this experimental study, We investigated histopathological and serological effects of melatonin and social stress (food deprivation and isolation) on different features of sperm and testicular tissue among 42 male rats in 7 groups including control, sham, melatonin received (M), food deprivation (FD), Food deprivation and melatonin treatment (FDM), Food deprivation and isolation situation (FDi), and Food deprivation and melatonin treatment and isolation situation (FDMi) groups. Epididymal sperms of all rats were also counted. Histopathological evaluation of the testes was done under a light microscopy to determine the number of spermiogenic cells. Serological evaluation of testosterone, corticosterone, and melatonin was performed, as well. For statistical analysis, oneway ANOVA and Tukey's post hoc test were used, and the value of p≤0.05 was considered statistically significance. RESULTS: The result showed that food deprivation increased the number of abnormal, immotile, and dead sperms, while decreased the number of normal sperms (p<0.05). Isolation could improve sperm motility and viability, while enhanced the number of sper- matogenic cells. Melatonin had a protective effect on sperm count, motility, and viability, while reduced sperm abnormality. CONCLUSION: Our results demonstrated that melatonin treatment and isolation situation improve the parameters related to epididymal sperms and spermatogenic cells after food deprivation.

Reversal of prenatal morphine exposure-induced memory deficit in male but not female rats.

Impaired memory performance in offspring is one of the long-lasting neurobehavioral consequences of prenatal opiate exposure. Here, we studied the effects of prenatal morphine exposure on inhibitory avoidance memory performance in male and female offspring and also investigated whether these deficits are reversible during the postnatal development. Pregnant Wistar rats received morphine sulfate through drinking water, from the first day of gestation up to the day 13, M1₋13, or to the time of delivery, M1₋21. Four- and ten-week-old (adolescent and adult, respectively) male and female offspring were subjected to behavioral assays and then analysis of proteins involved in apoptosis or in synaptic plasticity. Results revealed that adolescent and adult female rats failed in passive avoidance retention task in both M1₋13 and M1₋21 groups. Adolescent and adult male offspring were similar to control animals in M1₋13 group. However M1₋21 impaired retention task in prepubertal male offspring, and this memory loss was repaired in postpubertal stage. Consistently, Bax/Bcl-2 ratio and cleaved caspase-3 were significantly increased in both M1₋13 and M1₋21 adolescent and adult female rats, but only in M1₋21 adolescent male rats. Furthermore, prenatal morphine exposure reduced the expression of brain-derived neurotrophic factor precursor protein in adolescent and adult female offspring and also decreased p-ca(2+)/calmodulin-dependent kinase II/ca(2+)/calmodulin-dependent kinase II ratio in adolescent male and female rats. Altogether, the results show that prenatal morphine exposure, depending on the time or duration of exposure, has distinct effects on male and female rats, and postnatal development may reverse these deficits more likely in males.

Cyclooxygenase (COX)-1 activity precedes the COX-2 induction in Aß-induced neuroinflammation.

Two different isoforms of cyclooxygenases, COX-1 and COX-2, are constitutively expressed under normal physiological conditions of the central nervous system, and accumulating data indicate that both isoforms may be involved in different pathological conditions. However, the distinct role of COX-1 and COX-2 and the probable interaction between them in neuroinflammatory conditions associated with Alzheimer's disease are conflicting issues. The aim of this study was to elucidate the comparable role of each COX isoform in neuroinflammatory response induced by ß-amyloid peptide (Aß). Using histological and biochemical methods, 13 days after stereotaxic injection of Aß into the rat prefrontal cortex, hippocampal neuroinflammation and neuronal injury were confirmed by increased expression of tumor necrosis factor-alpha (TNF-α) and COX-2, elevated levels of prostaglandin E2 (PGE2), astrogliosis, activation of caspase-3, and neuronal cell loss. Selective COX-1 or COX-2 inhibitors, SC560 and NS398, respectively, were chronically used to explore the role of COX-1 and COX-2. Treatment with either COX-1 or COX-2 selective inhibitor or their combination equally decreased the level of TNF-α, PGE2, and cleaved caspase-3 and attenuated astrogliosis and neuronal cell loss. Interestingly, treatment with COX-1 selective inhibitor or the combined COX inhibitors prevented the induction of COX-2. These results indicate that the activity of both isoforms is detrimental in neuroinflammatory conditions associated with Aß, but COX-1 activity is necessary for COX-2 induction and COX-2 activity seems to be the main source of PGE2 increment.

Maternal oral consumption of morphine increases Bax/Bcl-2 ratio and caspase 3 activity during early neural system development in rat embryos.

Maternal morphine consumption has been shown to result in physical and neurobehavioral defects in fetus and offspring, but the underlying molecular mechanisms of these defects remain unclear. Regarding the critical role of apoptosis in normal development of central nervous system, the present study was designed to investigate the effect of intrauterine morphine exposure on programmed cell death of neuroblasts during the early development of neural system. Pregnant Wistar rats received morphine sulfate through drinking water at the concentration of 0.01 mg/ml (20 ml water per day for each rat) from the first day of gestation to the time of sampling. Control groups received tap water. Control and morphine-treated pregnant rats, each in five separated groups, were killed on gestational days 9.5 to 13.5, and the embryos were taken out, fixed, and embedded in paraffin. Immunohistochemical assay was used to reveal the protein expression of Bax, Bcl2, and the activation of caspase 3. The results showed a significant increase in Bax immunoreactivity in all of the mentioned embryonic days (E9.5 to E13.5) and a significant decrease in Bcl-2 immunoreactivity at days E10.5 and E12.5 in morphine-treated groups compared with control. Data analysis revealed that Bax/Bcl2 ratio was increased in all of the morphine-exposed groups. Consistent with these results, immunostaining of cleaved caspase 3 showed a significant increase at days E11.5 to E13.5. These findings suggest that morphine exposure during the first embryonic days may enhance the susceptibility of neuroblasts to apoptosis by upregulating the ratio of Bax to Bcl-2 protein expression and increasing downstream caspase-3 activity. The increased probability of neuroblast apoptosis may be the cause of morphine-induced defects in the central nervous system development and its structural and neurobehavioral consequences.

Effects of maternal oral morphine consumption on neural tube development in Wistar rats.

Opiate abuse during pregnancy may result in abnormal nervous system function. In order to evaluate the effects of morphine on the development of the nervous system, the present study focused on the effects of maternal morphine consumption on neural tube development in Wistar rats. Female Wistar rats (250-300 g) were crossed with male rats and coupling time was recorded (embryonic day 0-E0). Experimental groups received 0.1, 0.05, and 0.01 mg/ml of morphine in drinking water daily (14 ml water for each rat). Control group received tap water. On embryonic day 9.5 (E9.5), the animals were anesthetized and the embryos were surgically removed. The embryos were fixed in 10% formalin for 1 week. After this time, weights and lengths (antero-posterior axis--A-P) of the embryos were determined and then tissues were processed, sectioned, and stained in hematoxylin and eosin (H&E). The sections were investigated for neural tube development by light microscope and MOTIC software. The decrease in "A-P" length and embryonic weight for the group that received 0.01 mg/ml morphine was significant. It seems that daily consumption of morphine sulfate could delay neural tube development. In addition, administration of 0.01 mg/ml of morphine led to damage to the regulated neuro-ectoderm layer and its thickness. This study showed that oral morphine consumption leads to neural tube defects, as indicated in the morphometric change and also reduction in weight and length of the embryos. These defects might affect the behavior of the animals.