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Abstract QSPR mathematically links physicochemical properties with the structure of a molecule. The physicochemical properties of chemical molecules can be predicted using topological indices. It is an effective method for eliminating costly and time-consuming laboratory tests. We established a QSPR between mev-degree and mve-degree-based indices and the physical properties of benzenoid hydrocarbons. To compute these indices, we designed a program using Maple software and the correlation between indices and physical properties was developed using the SPSS software. Our study reveals that the mve-degree-based sum-connectivity $$(\chi ^{mve})$$ ( χ mve ) and atom bond connectivity ( $$ABC^{mve}$$ A B C mve ) index, mev-degree-based Randić ( $$R^{mev}$$ R mev ) and Zagreb ( $$M^{mev}$$ M mev ) index are the three most significant parameters and have good prediction ability for the physicochemical properties. We examined that $$R^{mev}$$ R mev predicts the molar refractivity and boiling point, $${\chi }^{mve}$$ χ mve predicts the LogP and enthalpy, $$ABC^{mve}$$ A B C mve predicts the molecular weight, $$M^{mev}$$ M mev predicts the Gibb’s energy, Pie-electron energy and Henry’s law. Moreover, we computed the indices for the linear [n]-phenylen.

Structures are recommended to be designed and constructed with the integration of structural health monitoring techniques to ensure that they can dissipate a large amount of energy without considerable damage when subjected to earthquakes. Hysteretic (H), friction (F), viscous (V), and viscoelastic (VE) dampers were employed in this study to observe the response of buildings using the commercially available software ETABS. The effect of different dampers along with configurations on three prototype concrete buildings (3, 5, and 10-storey) was studied by performing a time history analysis. Initially, the response of the buildings was observed in terms of storey drifts, base shear, and displacement without using dampers, while gradually increasing the damping ratio from 0 to 40%. Subsequently, the response of the buildings was evaluated in terms of displacements and base shear using various types of dampers with different configurations. The analysis results demonstrated that the effectiveness of viscous and viscoelastic dampers is higher for 3 and 5-storey buildings, while friction and hysteresis dampers are more suitable for 10-storey buildings. This information enables informed decisions regarding the performance and maintenance of dampers, contributing to the overall resilience and durability of structures in seismic events.

Introduction: RAD51D has been reported as a breast cancer (BC) and ovarian cancer (OC) predisposition gene, particularly among Caucasian populations. We studied the prevalence of RAD51D variants in Pakistani BC/OC patients. Materials and methods: In total, 371 young or familial BC/OC patients were thoroughly analyzed for RAD51D sequence variants using denaturing high-performance liquid chromatography pursued by DNA sequencing of differentially eluted amplicons. We also assessed the pathogenic effects of novel variants using in-silicoalgorithms. All detected RAD51D variants were investigated in 400 unaffected controls. Results: No pathogenic RAD51D variant was detected. However, we identified nine unique heterozygous variants. Of these, two missense variants (p.Pro10Leu and p.Ile311Asn) and one intronic variant (c.481-26_23delGTTC) were classified as in silico-predicted variants of uncertain significance (VUS), with a frequency of 0.8% (3/371). The p.Pro10Leu variant was detected in a 28-year-old female BC patient of Punjabi ethnic background, whose mother and maternal cousin had BCs at ages 53 and 40, respectively. This variant was also detected in 1/400 (0.25%) healthy controls, where the control subject’s daughter had acute lymphoblastic leukemia. The p.Ile311Asn variant was identified in a female BC patient at age 29 of Punjabi ethnicity and in 1/400 (0.25%) healthy controls, where the control subject’s daughter had Hodgkin’s disease at age 14. A novel intronic variant, c.481-26_-23delGTTC, was found in a 30-year-old Punjabi female BC patient but not in 400 healthy controls. Conclusion: No pathogenic RAD51D variant was identified in the current study. Our study data suggested a negligible association of RAD51D variants with BC/OC risk in Pakistani women.

Abstract Background BRCA1 and BRCA2 (BRCA1/2) are the most frequently investigated genes among Caucasian pancreatic cancer patients, whereas limited reports are available among Asians. We aimed to investigate the prevalence of BRCA1/2 germline variants in Pakistani pancreatic cancer patients. Methods One hundred and fifty unselected and prospectively enrolled pancreatic cancer patients were comprehensively screened for BRCA1/2 germline variants using denaturing high-performance liquid chromatography and high-resolution melting analyses, followed by DNA sequencing of the variant fragments. The novel variants were analyzed for their pathogenic effect using in-silico tools. Potentially functional variants were further screened in 200 cancer-free controls. Results Protein truncating variant was detected in BRCA2 only, with a prevalence of 0.7% (1/150). A frameshift BRCA2 variant (p.Asp946Ilefs*14) was identified in a 71-year-old male patient of Pathan ethnicity, with a family history of abdominal cancer. Additionally, we found a novel variant in BRCA2 (p.Glu2650Gln), two previously reported variants in BRCA1 (p.Thr293Ser) and BRCA2 (p.Ile2296Leu) and a recurrent nonsense variant in BRCA2 (p.Lys3326Ter). These variants were classified as variants of uncertain significance (VUS). It is noteworthy that none of these VUS carriers had a family history of pancreatic or other cancers. Conclusions In this first study, BRCA1/2 pathogenic variant is identified with a low frequency in pancreatic cancer patients from Pakistan. Comprehensive multigene panel testing is recommended in the Pakistani pancreatic cancer patients to enhance genetic understanding in this population.

Importance: Gastrointestinal (GI) cancers are the second leading cause of cancer-related deaths worldwide. Observations: The global challenges GI cancers pose are high, especially in middle- and low-income countries. Patients with these cancers present with symptoms of poor appetite, weight loss, heartburn, abdominal pain, fatigue, and anaemia. Several risk factors contribute to GI cancers, including age, gender, obesity, pathogenic infections, smoking cigarettes, alcohol consumption, and dietary habits. Most of these cancers are sporadic. However, some patients are at high risk because of a family history of GI cancers. Systemic diseases affect multiple organs, and their chronic occurrence elicits inflammatory responses at various sites. These diseases also contribute to GI cancers. Conclusion and Relevance: In this review, we discuss that untreated systemic diseases, including diabetes, hepatitis, AIDS, ulcers, and hypertension, can potentially lead to GI cancers if they remain untreated for a longer period. Systemic diseases initiate oxidative stress, inflammatory pathways, and genetic manipulations, which altogether confer risks to GI cancers. Here, we describe the association between systemic diseases and their underlying mechanisms leading to GI cancers.

For over a century, enzyme immobilisation has been proven to be a superior strategy to improve catalytic activity and reusability and ensure easy separation, easy operation, and reduced cost. Enzyme immobilisation allows for an easier separation of the enzyme from the reaction mixture, thus simplifying downstream processing. This technology protects the enzyme from degradation or inactivation by harsh reaction conditions, making it more robust and suitable to be used in various applications. Recent strategies of immobilisation methods, such as adsorption, cross-linking, entrapment or encapsulation, and covalent bonding, were critically reviewed. These strategies have shown promising results in improving enzyme stability, activity, and reusability in various applications. A recent development in enzyme immobilisation in nanomaterials and agrowaste renewable carriers is underlined in the current review. Furthermore, the use of nanomaterials and agrowaste carriers in enzyme immobilisation has gained significant attention due to their unique properties, such as high surface area, high mass transfer, biocompatibility, and sustainability. These materials offer promising outcomes for developing more efficient and sustainable immobilised enzymes. This state-of-the-art strategy allows for better control over enzyme reactions and enhances their reusability, leading to more cost-effective and environmentally friendly processes. The use of renewable materials also helps to reduce waste generation and promote the utilisation of renewable resources, further contributing to the development of a circular economy.

Ets-related gene (ERG) is overexpressed as a fusion protein in prostate cancer. During metastasis, the pathological role of ERG is associated with cell proliferation, invasion, and angiogenesis. Here, we hypothesized that miRNAs regulate ERG expression through its 3'UTR. Several bioinformatics tools were used to identify miRNAs and their binding sites on 3'UTR of ERG. The selected miRNAs expression was analyzed in prostate cancer samples by qPCR. The miRNAs overexpression was induced in prostate cancer cells (VCaP) to analyze ERG expression. Reporter gene assay was performed to evaluate the ERG activity in response to selected miRNAs. The expression of ERG downstream target genes was also investigated through qPCR after miRNAs overexpression. To observe the effects of selected miRNAs on cell proliferation and migration, scratch assay was performed to calculate the cell migration rate. miR-4482 and miR-3912 were selected from bioinformatics databases. miR-4482 and -3912 expression were decreased in prostate cancer samples, as compared to controls (p

To reduce the environmental pollution caused by cement manufacturing and to save both the economy and resources, it is required to use alternative waste materials of pozzolanic nature to partially replace cement in the construction industry. Among different cement replacement materials being used now-a-days, marble dust is the one on which limited research has been done especially on the performance of structural members likeRC slabs. In this paper, marble dust has been used in different ratios as partial replacement of cement in concrete mix. RC one-way slabs as well as plain concrete standard samples were cast to determine their mechanical properties i.e. compressive, tensile and flexural strengths, stiffness, first and ultimate load, crack patterns, modulus of elasticity, maximum deflection and durability etc. It was found that by increasing the dosage of marble dust in plain concrete samples, workability was decreased. Compressive and tensile strengths of concrete increased up to 7.5% replacement but decreased on further replacement. The permeability of concrete decreased with the addition of marble dust up to 10% replacement, then it increased. The behaviour of one-way slabs showed an increase in the first crack load and ultimate failure capacity. Moreover, decrease in the deflection of slabs was observed with the increasing replacement of cement with marble dust. The resistance of concrete against corrosion of steel reinforcement also increased due to less migration of chloride ions. Ultrasonic Pulse Velocity (UPV) tests showed improved homogeneity and stiffness of concrete structurewith the replacement of cement by marble dust.

Recently, the need of high living standards and developments in modern technology have significantly increased the usage of throwaway glass products. The use of these waste glass products in the production of construction materials (especially bricks) is ultimately very wholesome approach towards sustainable development. In this study, wasted glass up to 20% by weight was added to observe its impacts on bricks. The bricks containing powder glass were burnt along with ordinary bricks (with no powder glass) in same kiln and under same condition (type of fuel, temperature, duration etc.). The results illustrated that the properties of bricks vividly improved such as areal density, water absorption and efflorescence. The 20% increase of waste glass in the brick samples resulted in 14% decrease in areal density. The addition of fine powder glass filled the pores and reduced porosity of bricks. The substantial reduction in water absorption of 26.14% were observed with 20% addition of waste glass content. Also efflorescence was less in specimens having less quantity of waste glass burnt at higher temperatures. The present study presented a comprehensive analysis of waste glass as a mixing component for producing light weight sustainable bricks with improved water absorption properties.

Abstract Background The RecQ Like Helicase (RECQL) gene has previously been shown to predispose to breast cancer mainly in European populations, in particular to estrogen receptor (ER) and/or progesterone receptor (PR) positive tumor. Here, we investigated the contribution of pathogenic RECQL germline variants to hereditary breast cancer in early-onset and familial breast cancer patients from Pakistan. Methods Comprehensive RECQL variant analysis was performed in 302 BRCA1 and BRCA2 negative patients with ER and/or PR positive breast tumors using denaturing high-performance liquid chromatography followed by DNA sequencing. Novel variants were classified using Sherloc guidelines. Results One novel pathogenic protein-truncating variant (p.W75*) was identified in a 37-year-old familial breast cancer patient. The pathogenic variant frequencies were 0.3% (1/302) in early-onset and familial breast cancer patients and 0.8% (1/133) in familial patients. Further, three novel variants of unknown significance, p.I141F, p.S182S, and p.C475C, were identified in familial breast cancer patients at the age of 47, 68, and 47 respectively. All variants were absent in 250 controls. Conclusions Our data suggest that the RECQL gene plays a negligible role in breast cancer predisposition in Pakistan.

An experimental and analytical study was conducted to quantify the increase in strength and ductility of GFRP and CFRP confined concrete cylinders made of normal strength concrete and high strength concrete. The test data are also compared with theoretical predictions from three North American and European FRP design guidelines. The test results show that the effectiveness of both GFRP and CFRP is more pronounced in normal strength concrete compared to high strength concrete.

Abstract Background Pathogenic germline variants in MLH1, MSH2 and MSH6 genes account for the majority of Lynch syndrome (LS). In this first report from Pakistan, we investigated the prevalence of pathogenic MLH1/MSH2/MSH6 variants in colorectal cancer (CRC) patients. Methods Consecutive cases (n = 212) were recruited at the Shaukat Khanum Memorial Cancer Hospital and Research Centre (SKMCH&RC), between November 2007 to March 2011. Patients with a family history of > 3 or 2 HNPCC-associated cancers were classified as HNPCC (n = 9) or suspected-HNPCC (n = 20), respectively (group 1; n = 29). Cases with no family history were designated as non-HNPCC (group 2; n = 183). MLH1/MSH2/MSH6 genes were comprehensively screened in group 1. Pathogenic/likely pathogenic variants identified in group 1 were subsequently evaluated in group 2. Results Eight distinct pathogenic/likely pathogenic MLH1/MSH2 variants were found in group 1 (10/29; 34.5%), belonging to HNPCC (5/9; 55.6%) and suspected-HNPCC (5/20; 25%) families and in group 2 (2/183; 1.1%) belonging to non-HNPCC. Overall, three recurrent variants (MSH2 c.943-1G > C, MLH1 c.1358dup and c.2041G > A) accounted for 58.3% (7/12) of all families harboring pathogenic/likely pathogenic MLH1/MSH2 variants. Pathogenic MSH6 variants were not detected. Conclusion Pathogenic/likely pathogenic MLH1/MSH2 variants account for a substantial proportion of CRC patients with HNPCC/suspected-HNPCC in Pakistan. Our findings suggest that HNPCC/suspected-HNPCC families should be tested for these recurrent variants prior to comprehensive gene screening in this population.

Vibropressing compaction of dry mixed concrete has increased the production rate of paving blocks, as it eradicated the need of formwork to hold the fresh concrete mixture in shape after molding. This technique also optimized the cost-benefit ratio as it helps in achieving high strength blocks with the minimum utilization of water and cement. In this study, effect of steel slag powder (SSP) was studied as the cement replacement material on the physical and mechanical properties of paving blocks. The cement was replaced with SSP as 5%, 10%, 15%, 20%, 25% and 30% by mass. Incorporation of SSP improved the finishing of paving blocks. The results of compression testing revealed that paving blocks incorporating 5–15% SSP as the cement replacement showed higher strength than the control paving block. This improvement is entirely credited to the better packing of constituent particles caused by the filling effect of SSP. The increase in ultrasonic pulse speed also confirmed that 5–15% SSP improved the density of paving blocks. However, the impact toughness of paving blocks reduced with the rise in SSP percentage beyond 5%.

Pakistan’s agriculture and economy rely heavily on the Tarbela Reservoir. The present storage capacity of Tarbela is 8.2 BCM and it has been depleted by more than 40% due to sedimentation since 1976. It also has had a 0.94 percent (0.134 BCM) decrease in gross reservoir capacity every year. Historically, the amount of sediment trapped in the Tarbela Reservoir during the period 1976–2020 was 198.5 million tonnes annually. Based on the current operation by the Water and Power Development Authority (WAPDA), the delta is expected to extend to 2.41 km from the dam in 2035. The reservoir will become a run-of-the-river reservoir with a gross storage capacity of 2.87 BCM. This rapid loss of storage capacity will significantly impact reservoir benefits while also putting turbine performance at risk due to abrasion. Slowing the sediment deposition phenomena by a flexible operational strategy is a worthwhile aim from the dam manager’s viewpoint to achieve Sustainable Development Goals (i.e., poverty and hunger alleviation, clean affordable energy, protecting ecosystem etc.). Therefore, for the safe and long-term operation of the turbines, the existing Standard Operating Procedures (SOPs) adopted by WAPDA need to be appraised to delineate their impact on future optimized operations. The aspect of considering static SOPs on the whole period of reservoir operation has not been attempted earlier. The Tarbela Reservoir was selected as a case study to enhance the existing reservoir operation. The methodology relies upon the use of a 1-D sediment transport model in HEC-RAS to study the impact of the operational strategy on sedimentation. In conjunction, the existing reservoir operation of Tarbela was modelled in HEC-ResSim using its physical, operational, and 10-daily time-series data for simulation of releases and hydropower benefits based on a revised elevation-capacity curve for sedimentation. After calibration and validation, the model was applied to predict future reservoir operation impacts on a 5-year basis from 2025 to 2035 for determining storage capacity, irrigation releases, power production and energy generation. It was predicted that as the storage capacity of the reservoir is depleted (by application of the WAPDA current SOPs in future years), the irrigation releases would be increased in the Kharif season (April–September) by 7% and decreased by 50% in the Rabi season (October–March) with a corresponding increase in power generation by 4% and decrease by 37%, respectively, and the average annual energy generation would be decreased by 6.5%. The results showed that a gradual increase in the minimum operating level will slow down delta movement but it will reduce irrigation releases at times of high demand. The findings may assist water managers to improve the Tarbela Reservoir operation to achieve sustainable development goals and to attain societal future benefits.

BackgroundCancer patients are considered as highly vulnerable individuals in the current COVID-19 pandemic. We studied the clinical characteristics of survivor and non-survivor COVID-19-infected cancer patients in Pakistan.Patients and MethodsWe did a retrospective study of 70 cancer patients with PCR-confirmed COVID-19 infection from Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore and Peshawar, Pakistan between April 13 and July 09, 2020. These patients were discharged from the hospital or had died by July 09, 2020. Clinical, pathological and radiological characteristics were compared between survivors and non-survivors by fisher’s exact test and chi-square test. Univariable and multivariable logistic regression models were performed to explore the risk factors of mortality.ResultsSeventy cancer patients with SARS-CoV-2 infection were enrolled and the majority were males 38 (54.3%). 57 (81.4%) had solid tumors and 13 (18.6%) had hematological malignancies. Dyspnea (44 cases) was the most common symptom (62.9%). Complications were reported in 51 (72.9%) patients during the course of disease. 19 (27.1%) patients were admitted to an intensive care unit (ICU). A significant increase in the C-reactive protein level and neutrophil count was observed in the deceased patients as compared to the surviving patients. D-dimer values of ≥0.2 mg/L were significantly associated with mortality (P=0.01). We identified two independent risk factors associated with death, ICU admission (P=0.007) and D-dimer (P=0.003).ConclusionPakistani cancer patients with COVID-19 infection reported poor prognosis. Intensive surveillance of clinicopathological characteristics of cancer patients infected with COVID-19 especially D-dimer values may play a pivotal role in the outcome of the disease.

Abstract Background Pathogenic germline mutations in BRCA1 and BRCA2 (BRCA1/2) account for the majority of hereditary breast and/or ovarian cancers worldwide. To refine the spectrum of BRCA1/2 mutations and to accurately estimate the prevalence of mutation in the Pakistani population, we studied 539 breast cancer patients selected for family history and age of diagnosis. Methods Comprehensive screening for BRCA1/2 germline mutations was performed using state-of-the-art technologies. Results A total of 133 deleterious mutations were identified in 539 families (24.7%), comprising 110 in BRCA1 and 23 in BRCA2. The prevalence of BRCA1/2 small-range mutations and large genomic rearrangements was 55.4% (36/65) for families with breast and ovarian cancer, 27.4% (67/244) for families with two or more cases of breast cancer, 18.5% (5/27) for families with male breast cancer, and 12.3% (25/203) for families with a single case of early-onset breast cancer. Nine mutations were specific to the Pakistani population. Eighteen mutations in BRCA1 and three in BRCA2 were recurrent and accounted for 68.2% (75/110) and 34.8% (8/23) of all identified mutations in BRCA1 and BRCA2, respectively. Most of these mutations were exclusive to a specific ethnic group and may result from founder effects. Conclusions Our findings show that BRCA1/2 mutations account for one in four cases of hereditary breast/ovarian cancer, one in five cases of male breast cancer, and one in eight cases of early-onset breast cancer in Pakistan. Our study suggests genetic testing of an extended panel of 21 recurrent BRCA1/2 mutations for appropriately selected patients and their families in Pakistan.

Salient features of lightweight aggregate concrete (LAC) include noticeable fire resistance, high strength-to-weight ratio, and low magnitude of dead loads. Further, LAC has a low cost, eases construction practices, and possesses an environment-friendly nature. On the downside, LAC has substandard mechanical properties in comparison to normal aggregate concrete. Natural fiber-reinforced polymers (FRPs) have shown their potential in ameliorating the mechanical properties of natural aggregate concrete. So far, no study has been conducted to assess the efficacy of hemp rope confinement to strengthen lightweight aggregate concrete especially comprising rectilinear sections. This study aimed to overcome the substandard nature of LAC. A low-cost, sustainable, and environmentally green solution in the form of natural hemp rope layers is proposed. Twenty-four square concrete specimens were tested in three groups depending upon the presence and quantity of lightweight aggregates. It was found that concrete constructed with lightweight aggregates demonstrated lower ultimate compressive strength and strain as compared to normal aggregate concrete. Hemp rope-confined LAC showed enhanced ultimate compressive strength and strain. This enhancement was found to increase with the number of hemp rope layers. Several existing ultimate stress models were assessed to predict the ultimate compressive strength of the hemp rope-confined specimens. Only a single model was able to predict the ultimate compressive strength of the hemp rope-confined specimens with reasonable accuracy.

Reinforced concrete is used in the construction of bridges, buildings, retaining walls, roads, and other engineered structures. Due to seismic activities, a lot of structures develop seismic cracks. The rehabilitation of such structures is necessary for public safety. The overall aim of this research study was to produce a high-performance hybrid fiber-reinforced concrete (HPHFRC) with enhanced properties as compared to plain high-performance concrete and high-performance fiber-reinforced concrete (HPFRC) for the rehabilitation of bridges and buildings. Kevlar fibers (KF) and glass fibers (GF) with lengths of 35 mm and 25 mm, respectively, were added and hybridized to 1.5% by mass of cement to create hybrid fiber-reinforced concrete mixes. Eight mixes were cast in total. The compressive strength (f′c), flexural strength (fr), splitting tensile strength (fs), and other mechanical properties, i.e., energy absorption and toughness index values, were enhanced in HPHFRC as compared to CM and HPFRC. It was found that the concrete hybridized with 0.75% KF and 0.75% GF (HF-G 0.75 K 0.75) had the most enhanced overall mechanical properties, illustrating its potential to be utilized in the rehabilitation of bridges and structures.

Cement–clay Interlocking Hollow Brick Masonry (CCIHBM) walls are characterized by poor mechanical properties of bricks and mortar. Their performance is observed to be unsatisfactory under both gravity and seismic loads. There is an urgent need to develop sustainable, environmentally friendly, and low-cost strengthening materials to alter the structural behaviour of brick masonry walls in terms of strength and ductility. The results of an experimental investigation conducted on the diagonal compressive response of CCIHBM walls are presented in this study. In this experimental study, a total of six CCIHBM walls were constructed using cement–clay interlocking hollow bricks. One was tested as a control or reference wall, whereas the remaining walls were strengthened using cement mortar. In some walls, the cement mortar was also combined with the wire mesh. The research parameters included the type of Ordinary Portland Cement (OPC) (Type 1 and Type 2), thickness of cement mortar (10 mm and 20 mm), and layers of wire mesh (one and three layers). The experimental results indicate that control or unstrengthened CCIHBM walls failed in a very brittle manner at a very low ultimate load and deformation. The control CCIHBM wall, i.e., W-CON, failed at an ultimate load of 247 kN, and corresponding deflection was 1.8 mm. The strength and ductility of cement mortar and wire mesh-strengthened walls were found to be higher than the reference CCIHBM wall. For example, the ultimate load and deformation of cement-mortar-strengthened wall were found to be 143% and 233% higher than the control wall, respectively. Additionally, the ultimate failure modes of cement mortar and wire mesh strengthened were observed as ductile as compared to the brittle failure of reference wall or unstrengthened CCIHBM wall, which increased by 66% and 150% as compared with the control wall.

An amendment to this paper has been published and can be accessed via the original article.

A region on chromosome 19p13 is associated with the risk of developing ovarian and breast cancer. Here, the authors genotyped SNPs in this region in thousands of breast and ovarian cancer patients and identified SNPs associated with three genes, which were analysed with functional studies.

Breast cancer is a heterogeneous disease. Several genetic, environmental and lifestyle factors are involved in the aetiology of this disease. Genetic risk factors include alterations (mutations) in genes conferring risks to develop breast cancer. Depending on the associated lifetime risks of this malignancy, these genes are categorised into high-, moderate- and low-risk genes. Women carrying mutations in these genes are at an increased risk to develop breast cancer, ovarian cancer and several other malignancies. Breast carcinoma is the most reported malignancy in Pakistani females. Pakistan is a developing country with most of its population living in rural areas; hence, optimal healthcare facilities are inadequate for the early diagnosis and prevention of this disease. Hence, identification of individuals carrying mutations is clinically relevant as different strategies are available for the early detection, risk reduction and better management of this malignancy. This review summarises the findings of the major studies conducted in Pakistan to investigate the contribution of breast cancer predisposing genes. Furthermore, implications of the current studies and future research potentials are discussed. Key words: Breast cancer gene 1/2, breast cancer, checkpoint kinase 2, genetic susceptibility, Pakistan, RAD51C, tumour Protein p53, Vitamin D receptor

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Vitamin D is postulated to decrease the risk of breast cancer by inhibiting cell proliferation via the vitamin D receptor (VDR). Two common single nucleotide polymorphisms (SNPs) in the VDR gene, rs1544410 (BsmI) and rs2228570 (FokI), are inconsistently associated with breast cancer risk in Caucasian populations, while data for Asians are scarce. Here, we investigated the possible contribution of these SNPs to breast cancer risk in Pakistani breast cancer patients and in controls participating in a hospital-based breast cancer case-control study (PAK-BCCC).Genotyping of the BsmI and FokI SNPs was performed by PCR-based restriction fragment length polymorphism (RFLP) analysis of 463 genetically enriched female breast cancer cases with known BRCA1/2 status and in 1,012 controls from Pakistan. The association between SNP genotypes and breast cancer risk was investigated by logistic regression adjusted for potential breast cancer risk factors and stratified by BRCA1/2 status and family history. Odds ratios (ORs) and 95% confidence intervals (CIs) were reported.The b allele of the BsmI was associated with an increased breast cancer risk (per b allele OR 1.28, 95% CI 1.09-1.49, P = 0.003). Subgroup analysis revealed that this effect was restricted to BRCA1/2 non-carriers (per b allele OR 1.33, 95% CI 1.11-1.59, P = 0.002) and was stronger in those who reported a positive family history of breast and/or ovarian cancer (per b allele OR 1.64, 95% CI 1.20-2.22, P = 0.002). No association with breast cancer risk was detected for the FokI SNP.The BsmI polymorphism in the VDR gene may be associated with an increased breast cancer risk in Pakistani women negative for BRCA1/2 germline mutations.

Tumor cells induce an immunosuppressive microenvironment which leads towards tumor immune escape. Understanding the intricacy of immunomodulation by tumor cells is essential for immunotherapy. Indoleamine 2,3-dioxygenase (IDO) is an immunosuppressive enzyme which mediates tumor immune escape in various cancers including hepatocellular carcinoma (HCC). IDO up-regulation in HCC may lead to recruitment of regulatory T-cells into tumor microenvironment and therefore inhibit local immune responses and promote metastasis. HCC associated fibroblasts stimulate natural killer cells dysfunction through prostaglandin E2 and subsequently IDO promotes favorable condition for tumor metastasis. IDO up-regulation induces immunosuppression and may enhance the risk of hepatitis C virus and hepatitis B virus induced HCC. Therefore, IDO inhibitors as adjuvant therapeutic agents may have clinical implications in HCC. This review proposes future prospects of IDO not only as a therapeutic target but also as a prognostic marker for HCC., Competing Interests: Conflict-of-interest statement: Authors declare no conflict of interest for this manuscript.