Senescence is a major response to cancer chemotherapy and has been linked to unfavorable therapy outcomes. Lamin B1 is a component of the nuclear lamina that plays a pivotal role in chromatin stability. Downregulation of lamin B1 represents an established biomarker for cellular senescence. However, the protein expression level of lamin B1 in malignant tissue, particularly of the breast, has not been previously described. In this work, we investigated lamin B1 protein expression in normal breast epithelium, malignant breast tissue (including adjacent non-malignant tissue) and in malignant tissue exposed to neoadjuvant chemotherapy (NAC) using immunohistochemistry (IHC) in three patient groups (n = 15, n = 87, and n = 43, respectively). Our results indicate that lamin B1 mean positive expression was 93% in normal breast epithelium and 88% in malignant breast cells, but significantly decreased (mean: 55%, p < 0.001) in malignant breast tissue after exposure to NAC, suggestive of senescence induction. No significant association between lamin B1 expression and other clinicopathological characteristics or survival of breast cancer patients was recorded. To our knowledge, this is the first report that established the baseline protein expression level of lamin B1 in normal and malignant breast tissue, and its reduction following exposure to chemotherapy. In conclusion, lamin B1 downregulation can be used reliably as a component of multiple biomarker batteries to identify therapy-induced senescence (TIS) in clinical cancer.

Aptamers offer a great opportunity to develop innovative drug delivery systems that can deliver cargos specifically into targeted cells. In this study, a chimera consisting of two aptamers was developed to deliver doxorubicin into cancer cells and release the drug in cytoplasm in response to adenosine-5′-triphosphate (ATP) binding. The chimera was composed of the AS1411 anti-nucleolin aptamer for cancer cell targeting and the ATP aptamer for loading and triggering the release of doxorubicin in cells. The chimera was first produced by hybridizing the ATP aptamer with its complementary DNA sequence, which is linked with the AS1411 aptamer via a poly-thymine linker. Doxorubicin was then loaded inside the hybridized DNA region of the chimera. Our results show that the AS1411–ATP aptamer chimera was able to release loaded doxorubicin in cells in response to ATP. In addition, selective uptake of the chimera into cancer cells was demonstrated using flow cytometry. Furthermore, confocal laser scanning microscopy showed the successful delivery of the doxorubicin loaded in chimeras to the nuclei of targeted cells. Moreover, the doxorubicin-loaded chimeras effectively inhibited the growth of cancer cell lines and reduced the cytotoxic effect on the normal cells. Overall, the results of this study show that the AS1411–ATP aptamer chimera could be used as an innovative approach for the selective delivery of doxorubicin to cancer cells, which may improve the therapeutic potency and decrease the off-target cytotoxicity of doxorubicin.

Cisplatin and carboplatin are integral parts of many antineoplastic management regimens. Both platinum analogues are potent DNA alkylating agents that robustly induce genomic instability and promote apoptosis in tumor cells. Although the mechanism of action of both drugs is similar, cisplatin appears to be more cytotoxic. In this study, the genotoxic potential of cisplatin and carboplatin was compared using chromosomal aberrations (CAs) and sister-chromatid exchange (SCE) assays in cultured human lymphocytes. Results showed that cisplatin and carboplatin induced a significant increase in CAs and SCEs compared to the control group (p<0.01). Levels of induced CAs were similar in both drugs; however, the magnitude of SCEs induced by cisplatin was significantly higher than that induced by carboplatin (p<0.01). With respect to the mitotic and proliferative indices, both cisplatin and carboplatin significantly decreased mitotic index (p0.05). In conclusion, cisplatin was found to be more genotoxic than carboplatin in the SCE assay in cultured human lymphocytes, and that might explain the higher cytotoxicity of cisplatin.

Both opioids and cannabinoids have well-known antinociceptive effects in different animal models of chronic pain. However, unwanted side effects limit their use. The aim of this study is to evaluate the antinociceptive effect of combining synthetic cannabinoids with subtherapeutic doses of opioids, and to evaluate the effects of these drugs/combinations on rat’s locomotor activity. Intra-plantar injection of Complete Freund’s Adjuvant (CFA) into the left hindpaw and intraperitoneal injection of streptozotocin (STZ) were used to induce inflammatory and diabetic neuropathic pain in adult male Sprague-Dawley rats, respectively. Von Frey filaments were used to assess the antinociceptive effects of opioids (morphine and tramadol) and the synthetic cannabinoids (HU210 and WIN55212) or their combinations on CFA and STZ-induced mechanical allodynia. Open field test was used to evaluate the effect of these drugs or their combinations on locomotion. HU210 and WIN55212 did not produce significant antinociceptive effect on inflammatory pain while only the maximal dose of HU210 (1 mg/kg) was effective in neuropathic pain. Only the maximal doses of morphine (3.2 mg/kg) and tramadol (10 mg/kg) had significant anti-allodynic effects in both models. Tramadol (1 mg/kg) enhanced the antinociceptive effects of WIN55212 but not HU210 in neuropathic pain with no effect on inflammatory pain. However, in open field test, the aforementioned combination did not change tramadol-induced depression of locomotion. Tramadol and WIN55212 combination produces antinociceptive effects in neuropathic but not inflammatory pain at low doses with no additional risk of locomotor impairment, which may be useful in clinical practice.

Whole Exome Sequencing (WES) is a powerful approach for detecting sequence variations in the human genome. The aim of this study was to investigate the genetic defects in Jordanian patients with inherited retinal dystrophies (IRDs) using WES. WES was performed on proband patients’ DNA samples from 55 Jordanian families. Sanger sequencing was used for validation and segregation analysis of the detected, potential disease-causing variants (DCVs). Thirty-five putatively causative variants (6 novel and 29 known) in 21 IRD-associated genes were identified in 71% of probands (39 of the 55 families). Three families showed phenotypes different from the typically reported clinical findings associated with the causative genes. To our knowledge, this is the largest genetic analysis of IRDs in the Jordanian population to date. Our study also confirms that WES is a powerful tool for the molecular diagnosis of IRDs in large patient cohorts.