Characterization of TRAIL-mediated apoptotic pathways in the lung cancer cell line NCI-H460 with focus on caspase-3 and XIAP

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily of cytokines, was discovered in mid-90s. Due to its unique capability of selectively killing tumor cells without affecting normal tissues, it gained much attention as a potential tumor therapeutic. Intensive research has been done during the last two decades to utilize the natural cytokine and derived molecules thereof as effective death inducer for cancer therapy. Unfortunately a big hurdle is the primary or acquired resistance of many tumor cells to TRAIL. Since TRAIL can activate both the extrinsic as well as the intrinsic pathway of apoptosis, blocking the intrinsic mitochondrial amplification loop in so-called type II cells can confer apoptosis resistance to TRAIL

Current perspectives of oncoplastic breast surgery in Pakistan

Oncoplastic breast surgery is based on the concept of tumour-specific immediate reconstruction. It combines both local and distant techniques to maintain breast texture, symmetry and cosmesis without compromising oncological outcome. The current narrative review was planned to highlight the current state and future of oncoplastic breast surgery in low- and middle-income countries where its utilisation in surgical practice remains insubstantial because majority of the surgeons who are treating breast cancer are either general surgeons or breast surgeons who do not have expertise in oncoplastic breast surgery or reconstructive surgery. Moreover, scarcity of financial resources, ignorance about oncoplastic breast surgery techniques, disfigurement distress and cultural taboos coerce women to hide in the shadows with their breast disease. Oncoplastic breast surgery needs more exposure in a developing country like Pakistan. There is a need to establish dedicated oncoplastic breast surgery training centres, fellowship programmes, workshops, and webinars to incorporate such techniques in the practice of breast surgeons

Outcomes of oncoplastic breast surgery compared to breast-conserving surgery in breast cancer patients in a developing country: A retrospective cohort study

Background and Objective: Breast-conserving surgery (BCS) with adjuvant radiotherapy remains the standard of care for early breast cancers in Pakistan. We sought to compare the outcomes of BCS with oncoplastic surgery (OPS), a relatively infrequent approach to breast cancer treatment in the country.Methods: This retrospective cohort study was conducted at Aga Khan University Hospital and Ziauddin Hospital in Karachi. Patients who had biopsy-proven Stage-I to III breast cancer and underwent either OPS or BCS between August 1, 2016, and December 31, 2021, were identified and followed for 30 days. Data were collected by reviewing patient files and electronic records.Results: A total of 481 patients were included in the study, where 204 (42.4%) underwent BCS and 277 (57.6%) underwent OPS. Mean tumor volume (146.8 vs. 90.4 cm3), and postoperative complications (2.2 % vs. 0%) were higher in OPS while the frequency of positive margins was greater in the BCS group (15.7 % vs. 2.2 %). There were no significant differences in the histologic type of tumor between the two groups.Conclusion: OPS is a valid alternative approach to breast cancer treatment that can be offered to women with early stage, locally advanced, multifocal or tumors at complex locations owing to the reduced occurrence of positive margins and thus lowered re-excision rates

Breast surgery super-specialization: Impact on advanced surgical training and research

The earliest records of breast cancer (BC) date back to 3,000 - 2,500 B.C., ever since multiple curative options have been explored. First known wide margin excision was performed around 1st Century AD and a prototype of the modern-day BC surgery, Halsted radical mastectomy, was performed in the 20th Century. BC is the most common cancer in Pakistan accounting for up to 14.5% of the total cancer incidences. Accredited breast surgery fellowships were established in the UK and USA in 2002 and 2003, respectively. In Pakistan, the movement was delayed and the two-year College of Physicians and Surgeons Pakistan (CPSP) accredited breast surgery fellowship program started in 2019. The increasing annual incidence and changes in demands have led to an increased percentage of General Surgery graduates taking up specialty training. PubMed search from 1990 to 2021 showed a rising trend in the number of breast cancer publications from Pakistan; from almost no papers before 1990 to 615 between 2012 to 2021. This remarkable surge in BC-related research can be explained by the commencement of fellowship programs in breast surgery and related fields. An increase in specialist training will yield better results in the management of patients, improve clinical trials and help produce more meaningful publications from the country

An initial experience of using dual energy contrast enhanced mammography at a tertiary care hospital in Pakistan

Objective: Contrast enhanced mammography (CEM), a relatively new and promising modality, combines mammography (MMG) with an iodinated contrast material to illuminate neovascularity within the breast; analogous to magnetic resonance imaging (MRI). CEM improves the overall sensitivity of MMG; reduces the need for unnecessary biopsies and follow-up imaging and can be considered a reasonable substitute for MRI. In Pakistan, CEM was recently introduced and to assess its usability a study was conducted on five patients before making it available as a regular investigation.Case presentations: Four out of the five patients had a clinical suspicion of malignancy with two patients having heterogeneously dense breasts and two with dense breasts. All enhancing lesions were concordant on biopsy and had similar corresponding findings on additional imaging such as ultrasound (US) and/or MRI. CEM in all four cases of biopsy proven malignancy facilitated surgical planning. The fifth patient underwent CEM for screening and was found to have no enhancing lesionConclusion: In low-middle-income countries (LMICs) where breast MRI is not readily available and expensive for the populace, CEM can be a reliable alternative. The initial experience with CEM at our hospital shows better visualization of malignant lesions in dense and heterogeneously dense breasts with an easy-to-perform technique and a shorter imaging time while facilitating surgical decision-making in terms of breast conservation

Bcl-2-mediated control of TRAIL-induced apoptotic response in the non-small lung cancer cell line NCI-H460 is effective at late caspase processing steps.

Dysregulation of the mitochondrial signaling pathway of apoptosis induction represents a major hurdle in tumor therapy. The objective of the presented work was to investigate the role of the intrinsic (mitochondrial) apoptotic pathway in the non-small lung cancer cell line NCI-H460 upon induction of apoptosis using the highly bioactive TRAIL derivative Db-scTRAIL. NCI-H460 cells were TRAIL sensitive but an only about 3 fold overexpression of Bcl-2 was sufficient to induce a highly TRAIL resistant phenotype, confirming that the mitochondrial pathway is crucial for TRAIL-induced apoptosis induction. TRAIL resistance was paralleled by a strong inhibition of caspase-8, -9 and -3 activities and blocked their full processing. Notably, especially the final cleavage steps of the initiator caspase-8 and the executioner caspase-3 were effectively blocked by Bcl-2 overexpression. Caspase-9 knockdown failed to protect NCI-H460 cells from TRAIL-induced cell death, suggesting a minor role of this initiator caspase in this apoptotic pathway. Rather, knockdown of the XIAP antagonist Smac resulted in enhanced caspase-3 degradation after stimulation of cells with TRAIL. Of note, downregulation of XIAP had only limited effects on TRAIL sensitivity of wild-type NCI-H460 cells, but resensitized Bcl-2 overexpressing cells for TRAIL-induced apoptosis. In particular, XIAP knockdown in combination with TRAIL allowed the final cleavage step of caspase-3 to generate the catalytically active p17 fragment, whose production was otherwise blocked in Bcl-2 overexpressing cells. Together, our data strongly suggest that XIAP-mediated inhibition of final caspase-3 processing is the last and major hurdle in TRAIL-induced apoptosis in NCI-H460 cells, which can be overcome by Smac in a Bcl-2 level dependent manner. Quantitative investigation of the XIAP/Smac interplay using a mathematical model approach corroborates our experimental data strengthening the suggested roles of XIAP and Smac as critical determinants for TRAIL sensitivity

Breast cancer in a teenage girl with BRCA mutation: A case report from a low middle-income country

Introduction: A staggering majority of pediatric breast masses are benign (mostly fibroadenoma) and so a biopsy is not readily performed as it can potentially lead to a future breast disfigurement. However, this should not be standard practice as this can lead to a delayed diagnosis, and hence, the treatment of pediatric breast cancer (BC); this was also seen in our patient\u27s scenario.Case history: Here, we report the case of the youngest known breast cancer patient in Pakistan, a 15-year-old girl. The right-sided breast lump which was diagnosed clinically as a fibroadenoma later turned out to be stage IIb pT3N0M0 metaplastic breast carcinoma with BRCA1 positivity and mutations in SMARCA4. Being young and unmarried, the patient and her family decided to opt for breast-conserving surgery with high-risk surveillance for breast and ovaries.Discussion: We believe that prophylactic surgeries can be delayed with strict surveillance and thorough counseling. As pediatric BC is linked to a less favorable prognosis, every young patient diagnosed with breast cancer and their family should undergo genetic testing. BC management should be handled by specialists in the field and doctors should be trained for initial diagnostics and timely referral of patients.Conclusion: It is important to improve our understanding of genetic predisposition and testing in lower-middle-income countries. Considering the changing global trends, we suggest that the utilization of genetic services is direly needed to improve preventative care for at-risk individuals with breast and other cancers

Comparative Study of Protective Effect of Cimetidine and Verapamil on Paracetamol-Induced Hepatotoxicity in Mice

Paracetamol, chemically known as acetaminophen, if taken in higher doses has hepatotoxic potential. Cimetidine by inhibiting the cytochromal enzymes and reducing the production of the toxic metabolite can reduce the hepatotoxic potential while Verapamil can act as a hepatoprotective by maintaining calcium homeostasis. The present study was conducted to study the hepatoprotective activity of Cimetidine and Verapamil against the toxicity induced by paracetamol. In addition to the group receiving only distilled water or 300 mg/kg paracetamol additional groups were added treated with 150 mg/kg Cimetidine and Verapamil alone or both. The Liver function tests and histopathology revealed hepatotoxicity in the group receiving paracetamol (PCM) while normal parameters were observed in the groups receiving Cimetidine and Verapamil. Our results strongly suggested that Cimetidine and Verapamil possess hepatoprotective potential against paracetamol induced hepatotoxicity

Clinicopathological features and survival outcomes of metaplastic breast carcinoma - an observational multi-centric study

Purpose: To describe the clinicopathological features, and subtypes of metaplastic breast cancer (MpBC) in Pakistan and further to understand its response to treatment, including region-specific survival outcomes. Patients and methods: This retrospective cohort study was conducted at two private tertiary care hospitals in Karachi, Pakistan. Our selection criteria included a total of 215 patients who were diagnosed with MpBC at an age older than 18 years from 1994 to 2021. Data regarding clinicopathological features, staging, receptor status, treatment modalities, recurrence, and survival was obtained. Death was scored as an event, and patients who were alive were censored at the time of the last follow-up. Results: The incidence of MpBC at our study centers is 3.21%. The median age of diagnosis was 50 years (range 22 to 80 years) and most patients presented at Stages II (45.1%) and III (44.2%). Among patients who received neoadjuvant chemotherapy, 31.7% achieved complete pathological response. The 3-year survival of those who received neoadjuvant chemotherapy was 96%. During our study, 19.1% of patients died and the median survival duration was 9 years 7 months 9 days. Survival of patients was significantly lower in patients who had metastasis (p-value = 0.042) and those who had tumor recurrence (p-value = 0.001). Conclusion: Metaplastic breast cancer is an extremely rare variant of breast cancer with features that exist as a spectrum. Our study demonstrated considerable success with the use of neoadjuvant chemotherapy. The pathological complete response achieved in our study is one of the highest ever reported. Our success, though limited, warrants further research in the use of neoadjuvant chemotherapy in MpB