Expression Of Tumour Markers And Determination Of Microvessel Density In Mnu-Induced Breast Tumour

Angiogenesis plays an important role in breast tumour development. In this study, breast tumours were induced by injecting rats intraperitoneally with 1-methyl-1-nitrosurea (MNU) at dose of 70 mg/kg body weight in 3 consecutive days into 21-days old rats. Angiogenesis memainkan peranan penting dalam perkembangan tumor payudara.Untuk kajian ini, pengaruhan tumor payudara dilakukan melalui suntikan karsinogen MNU (1-methyl-1-nitrosurea) pada tikus berumur 21 hari

Cytoplasmic and nuclear HER4 expression in HER2 negative breast cancer cell lines

HER4 cleavage and its subcellular localisations have been previously proven to mediate anti-HER2 resistance. The description of the HER4 subcellular localisations in HER2 negative breast cancer, on the other hand, is incomplete. The objective of this study was to determine the cytoplasmic and nuclear expression of HER4 in HER2 negative breast cancer cell lines in order to gain a better understanding of the key features of HER4 signalling in the context of anti-HER2 resistance. MCF-7 and MDA-MB-231 cells were cultured for 48 h at 37 °C and 5% CO2 in fresh DMEM medium with 10% foetal bovine serum and 1% penicillin-streptomycin. The western blot analysis for HER4 protein was done on cytoplasmic and nuclear extracts that had been obtained previously using the NE-PER Nuclear and Cytoplasmic Extraction Kit. Cytoplasmic and nuclear HER4 proteins were expressed in a variety of sizes, including 120 kDa, 55 kDa, 50 kDa, and 43 kDa. MCF-7 cells expressed significantly more cytoplasmic HER4120kDa than MDA-MB-231 cells. MCF-7 exhibited a single nuclear HER4 variant with a molecular weight of 50 kDa, whereas MDA-MB-231 expressed two nuclear HER4 variants with molecular weights of 50 kDa and 43 kDa. In comparison to MDA-MB-231 cells, MCF-7 cells exhibit higher level of cytoplasmic HER4120kDa with positive nuclear HER450kDa expression. Due to the presence of ER and PR in MCF-7, it is important to investigate if the interaction of these HER4 variants with ER and PR confers resistance to anti-HER2 treatment on breast cancer. Meanwhile, results from MDA-MB-231 cells indicate that nuclear HER4 contributes to the development of TNBC

Potential association of nicotinamide on the telomerase activity and telomere length mediated by PARP-1 mechanism in myeloid cancer

Administration of nicotinamide is affecting various types of cells through its survival, maturation, and differentiation. Nicotinamide as part of vitamin B3, plays an important role in DNA repair and maintenance of the genomic stability which related to its function as a NAD+ precursor that involve in many biological processes. During DNA breaks, PARP-1 mechanism will be activated and use NAD+ as a substrate in process of DNA damage and repair that will result to either cell repair and cell death. In the meantime, in presence of nicotinamide that is also acting as a PARP-1 inhibitor, causing inability of the repair mechanism to fix the entire DNA damage which also lead to the cell death. Therefore, loss of PARP-1 enzyme will cause disturbance in the DNA repair process. Telomere shortening rate was reduced in the presence of nicotinamide that might related with telomerase enzyme which able to maintain the telomere length of the cell. Other than that, telomere also can be influenced by PARP-1 activity where it might show some correlation between nicotinamide, telomere and telomerase that could related with PARP-1 mechanism. Currently, there is no treatment options that respond effectively in chronic myeloid leukemia (CML) in blast crisis (BC) phase without any side effect and it is require an identification of new drug therapies to treat the CML patients. By understanding the role and potential of nicotinamide relation with PARP-1 mechanism in telomere and telomerase status may improve the therapeutic strategy for chronic myeloid leukemia

Neratinib could be effective as monotherapy or in combination with trastuzumab in HER2-low breast cancer cells and organoid models

BACKGROUND: Previous studies have suggested that patients with HER2-low breast cancers do not benefit from trastuzumab treatment although the reasons remain unclear.METHODS: We investigated the effect of trastuzumab monotherapy and its combination with different HER2 targeting treatments in a panel of breast cancer cell lines and patient-derived organoids (PDOs) using biochemical methods and cell viability assays.RESULTS: Compared to sensitive HER2 over-expressing (IHC3 + ) breast cancer cells, increasing doses of trastuzumab could not achieve IC50 in MDA-MB-361 (IHC 2 + FISH + ) and MDA-MB-453 (IHC 2 + FISH-) cells which showed an intermediate response to trastuzumab. Trastuzumab treatment induced upregulation of HER ligand release, resulting in the activation of HER receptors in these cells, which could account for their trastuzumab insensitivity. Adding a dual ADAM10/17 inhibitor to inhibit the shedding of HER ligands in combination with trastuzumab only showed a modest decrease in the cell viability of HER2-low breast cancer cells and PDOs. However, the panHER inhibitor neratinib was an effective monotherapy in HER2-low breast cancer cells and PDOs, and showed additive effects when combined with trastuzumab.CONCLUSION: This study demonstrates that neratinib in combination with trastuzumab may be effective in a subset of HER2-low breast cancers although further validation is required in a larger panel of PDOs and in future clinical studies.</p

Neratinib could be effective as monotherapy or in combination with trastuzumab in HER2-low breast cancer cells and organoid models

Background: Previous studies have suggested that patients with HER2-low breast cancers do not benefit from trastuzumab treatment although the reasons remain unclear. Methods: We investigated the effect of trastuzumab monotherapy and its combination with different HER2 targeting treatments in a panel of breast cancer cell lines and patient-derived organoids (PDOs) using biochemical methods and cell viability assays. Results: Compared to sensitive HER2 over-expressing (IHC3 + ) breast cancer cells, increasing doses of trastuzumab could not achieve IC50 in MDA-MB-361 (IHC 2 + FISH + ) and MDA-MB-453 (IHC 2 + FISH-) cells which showed an intermediate response to trastuzumab. Trastuzumab treatment induced upregulation of HER ligand release, resulting in the activation of HER receptors in these cells, which could account for their trastuzumab insensitivity. Adding a dual ADAM10/17 inhibitor to inhibit the shedding of HER ligands in combination with trastuzumab only showed a modest decrease in the cell viability of HER2-low breast cancer cells and PDOs. However, the panHER inhibitor neratinib was an effective monotherapy in HER2-low breast cancer cells and PDOs, and showed additive effects when combined with trastuzumab. Conclusion: This study demonstrates that neratinib in combination with trastuzumab may be effective in a subset of HER2-low breast cancers although further validation is required in a larger panel of PDOs and in future clinical studies

Obesity: A Prerequisite for Major Chronic Illnesses

Obesity is rampantly soaring at an alarming rate globally and simultaneously causing an increased incidence, and predisposition to various comorbidities. obesity is body mass index of >30kg/m2, while <18kg/m2 is underweight. The world at large fails to recognize obesity as an inevitable disease that requires strict measures to control this modifiable risk factor. W.H.O news release reported that over one billion people globally are obese among which 650 million were adults, 340 million were adolescents, and 39 million were children. The lowest obesity prevalence was reported in Timor Leste at 3.80%, Bangladesh at 3.60%, and Vietnam at 2.10% while the highest were noted in Nauru at 61%, cook island at 55.9%, and Palau at 55.3%. obesity is the most prevailing health problem (15% globally) associated with an increased propensity for development of several medical illnesses, obesity-associated adverse outcomes causing fatal complications that are difficult to manage, and premature mortality. The obese often feel they are not socially cared for by society and are accorded limited time by physicians who don’t view their health concerns from their own perspectives. Thus, making them pessimistic from low self-esteem and discrimination, body shaming, and stigmatization. They eventually develop depressive-anxiety disorder because of distrust insight

The role of HER4 in relation to trastuzumab resistance and prognosis in HER2 positive breast cancer

Background Trastuzumab resistance imposes a major limitation to the successful treatment of HER2 positive breast cancer. The expression of HER4 and its prognostic value is controversial in breast cancer. Furthermore, its role in trastuzumab treatment and resistance in HER2 positive breast cancer has not been reported. Methods The effects of trastuzumab on HER4 cleavage and its localisation were studied in both parental and trastuzumab-resistant SKBR3 and BT474 cells using western blot, RT-PCR, nuclear fractionation and confocal microscopy. Tissue microarrays consisting of a cohort of HER2 positive breast cancer patients were stained for HER4 by immunohistochemistry and the results were correlated with patients’ outcome. This study also assessed HER4 expression in the tumor samples from a window study of trastuzumab alone or in combination with neoadjuvant chemotherapy in HER2 positive breast cancer patients. Results Trastuzumab treatment upregulated HER4 mRNA, and increased expression of both 80 and 180 kDa HER4 protein isoforms, and induced nuclear translocation of 80kDa HER4 protein isoforms, which the results similar to heregulin stimulation. This was also seen in trastuzumab resistant cells although HER480kDa and nuclear HER4 decreased upon overnight withdrawal of trastuzumab in resistant cell lines. In addition, knockdown of HER4 protein expression by specific siRNAs increased trastuzumab sensitivity and reversed trastuzumab resistance in SKBR3 and BT474 cells, confirming the importance of HER4 in trastuzumab response. This study also showed that trastuzumab-induced HER4 nuclear translocation is due to HER4 activation and cleavage since γ-secretase inhibitor (GSi) and neratinib prevented the process when combined with trastuzumab treatment, correlating with an increased apoptosis and decreased cell viability. There was also increased nuclear HER4 expression in tumors from both BT474 xenografts and from patients with breast cancer treated with trastuzumab monotherapy. Furthermore, nuclear HER4 predicted poor clinical response to trastuzumab monotherapy in patients undergoing a window study and was a poor prognostic factor in HER2 positive breast cancer. Conclusions This study suggests HER4 activation, cleavage and nuclear translocation play a key role in trastuzumab resistance in HER2 positive breast cancer. Nuclear HER4 could be a novel predictive and prognostic biomarker in HER2 positive breast cancer patients.</p

The role of HER4 in relation to trastuzumab resistance and prognosis in HER2 positive breast cancer

Background Trastuzumab resistance imposes a major limitation to the successful treatment of HER2 positive breast cancer. The expression of HER4 and its prognostic value is controversial in breast cancer. Furthermore, its role in trastuzumab treatment and resistance in HER2 positive breast cancer has not been reported. Methods The effects of trastuzumab on HER4 cleavage and its localisation were studied in both parental and trastuzumab-resistant SKBR3 and BT474 cells using western blot, RT-PCR, nuclear fractionation and confocal microscopy. Tissue microarrays consisting of a cohort of HER2 positive breast cancer patients were stained for HER4 by immunohistochemistry and the results were correlated with patients’ outcome. This study also assessed HER4 expression in the tumor samples from a window study of trastuzumab alone or in combination with neoadjuvant chemotherapy in HER2 positive breast cancer patients. Results Trastuzumab treatment upregulated HER4 mRNA, and increased expression of both 80 and 180 kDa HER4 protein isoforms, and induced nuclear translocation of 80kDa HER4 protein isoforms, which the results similar to heregulin stimulation. This was also seen in trastuzumab resistant cells although HER480kDa and nuclear HER4 decreased upon overnight withdrawal of trastuzumab in resistant cell lines. In addition, knockdown of HER4 protein expression by specific siRNAs increased trastuzumab sensitivity and reversed trastuzumab resistance in SKBR3 and BT474 cells, confirming the importance of HER4 in trastuzumab response. This study also showed that trastuzumab-induced HER4 nuclear translocation is due to HER4 activation and cleavage since &gamma;-secretase inhibitor (GSi) and neratinib prevented the process when combined with trastuzumab treatment, correlating with an increased apoptosis and decreased cell viability. There was also increased nuclear HER4 expression in tumors from both BT474 xenografts and from patients with breast cancer treated with trastuzumab monotherapy. Furthermore, nuclear HER4 predicted poor clinical response to trastuzumab monotherapy in patients undergoing a window study and was a poor prognostic factor in HER2 positive breast cancer. Conclusions This study suggests HER4 activation, cleavage and nuclear translocation play a key role in trastuzumab resistance in HER2 positive breast cancer. Nuclear HER4 could be a novel predictive and prognostic biomarker in HER2 positive breast cancer patients.This thesis is not currently available in OR

Forensic short tandem repeat markers alteration in cancerous tissues: a scoping review

Abstract Background Short Tandem Repeats (STRs) are segments of DNA composed of a short sequence of nucleotides that repeat consecutively. These repeating sequences exhibit distinct lengths and nucleotide sequences among individuals, showcasing high variability and uniqueness. The STR profile remains consistent across all cells in an individual’s body. Nonetheless, changes in the STR profile have been documented in cancerous tissues. This scoping review aimed to investigate the occurrence and pattern of forensic STR markers alterations in cancerous tissues. We conducted a scoping review of the English-language publications published between 2002 and 2022 in the PubMed, Science Direct, and Scopus databases and a manual search of reference lists from reviewed papers. The review was carried out in compliance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews. Results Our search resulted in a total of 1,065 articles associating forensic STR studies with cancerous tissues. A total of 18 of these studies met our inclusion criteria. The D18S51 marker was most often found to be altered when associated with cancers such as breast, colorectal, gastric, gynaecology, and lung cancers. Following with that, FGA, VWA, D19S433, and D13S317 markers could as well be seen to have allelic alteration in cancerous tissues. Four other STR markers (TPOX, D7S820, D2S1338, and Penta D) could be potentially represented as stable STR markers in cancerous tissues. Conclusions According to our review, colorectal cancer tissue has the highest level of genomic instability compared to that of other cancer types. In summary, the genetic instability caused by faulty DNA mismatch repair processes in human carcinomas can pose challenges for forensic genotyping and DNA profile matching

The Unique Biology behind the Early Onset of Breast Cancer

Breast cancer commonly affects women of older age; however, in developing countries, up to 20% of breast cancer cases present in young women (younger than 40 years as defined by oncology literature). Breast cancer in young women is often defined to be aggressive in nature, usually of high histological grade at the time of diagnosis and negative for endocrine receptors with poor overall survival rate. Several researchers have attributed this aggressive nature to a hidden unique biology. However, findings in this aspect remain controversial. Thus, in this article, we aimed to review published work addressing somatic mutations, chromosome copy number variants, single nucleotide polymorphisms, differential gene expression, microRNAs and gene methylation profile of early-onset breast cancer, as well as its altered pathways resulting from those aberrations. Distinct biology behind early-onset of breast cancer was clear among estrogen receptor-positive and sporadic cases. However, further research is needed to determine and validate specific novel markers, which may help in customizing therapy for this group of patients