Mutational landscape of head and neck squamous cell carcinomas in a South Asian population

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer type globally and contributes significantly to burden of disease in South Asia. In Pakistan, HNSCC is anmong the most commonly diagnosed cancer in males and females. The increasing regional burden of HNSCC along with a unique set of risk factors merited a deeper investigation of the disease at the genomic level. Whole exome sequencing of HNSCC samples and matched normal genomic DNA (n=7) was performed. Significant somatic single nucleotide variants (SNVs) were identified and pathway analysis performed to determine frequently affected signaling pathways. We identified significant, novel recurrent mutations in ASNS (asparagine synthetase) that may affect substrate binding, and variants in driver genes including TP53, PIK3CA, FGFR2, ARID2, MLL3, MYC and ALK. Using the IntOGen platform, we identified MAP kinase, cell cycle, actin cytoskeleton regulation, PI3K-Akt signaling and other pathways in cancer as affected in the samples. This data is the first of its kind from the Pakistani population. The results of this study can guide a better mechanistic understanding of HNSCC in the population, ultimately contributing new, rational therapeutic targets for the treatment of the disease

The Spread of HIV in Pakistan: Bridging of the Epidemic between Populations

In the last two decades, ‘concentrated epidemics’ of human immunodeficiency virus (HIV) have established in several high risk groups in Pakistan, including Injecting Drug Users (IDUs) and among men who have sex with men (MSM). To explore the transmission patterns of HIV infection in these major high-risk groups of Pakistan, 76 HIV samples were analyzed from MSM, their female spouses and children, along with 26 samples from a previously studied cohort of IDUs. Phylogenetic analysis of HIV gag gene sequences obtained from these samples indicated a substantial degree of intermixing between the IDU and MSM populations, suggesting a bridging of HIV infection from IDUs, via MSM, to the MSM spouses and children. HIV epidemic in Pakistan is now spreading to the female spouses and offspring of bisexual MSM. HIV control and awareness programs must be refocused to include IDUs, MSM, as well as bisexual MSM, and their spouses and children

Successes and failures in tracheal bioengineering: Lessons learned

Background: Controversy in tracheal reconstruction using grafts and bioengineered constructs highlights the importance of animal studies before human application. Small animal models help to refine designs, but do not adequately model sizes relevant to human anatomy. We have conducted extensive large animal studies and summarize our findings in 26 consecutive transplants.Methods: We pooled 26 large animal studies together to investigate common elements related to successes and failures. In general, the engineered tracheal graft consisted of a decellularized extracellular matrix (ECM) surgical patch supported by a 3D printed plastic polymer scaffold. Circumferential graft coverage ranged from 50% to 100%, spanning the length of 4-6 tracheal rings. Some grafts included embedded stem cells. Control grafts were fabricated without the support scaffold. At death, grafts were harvested and examined grossly and through histology.Results: The support scaffold prevented graft malacia and collapse. Luminal epithelialization was most extensive in grafts with smaller circumferential coverage. Smaller circumferential coverage was also associated with longest animal survival. Chondrogenesis was only observed in grafts with embedded stem cells. Survival time was shortest in 100% circumferential grafts. Granulation tissue was an issue for all graft designs.Conclusions: Large animal models capture challenges and complexities relevant to human anatomy. Development of granulation tissue remains a challenge, especially in circumferential grafts. Significant additional research is needed to investigate granulation tissue formation and to provide actionable insight into its management

ML Phylogenetic tree of HIV-1 A Pakistani strains.

<p>ML trees where obtained with the ML method using the best fitting nucleotide substitution model. Branch lengths are scaled in nucleotide substitutions per site according to the bar at the bottom of each tree. Each tree includes the newly sequenced strains from Pakistan as well as reference strains from the HIV databases. Branches in each tree are colored according to the color legend in the figure. Pakistani sequences were labeled according to risk behavior as follows: M = male having sex with male (MSM), MS = spouses with infected partner, MC = MSM children with infected parent(s) and M-IDU = MSM who were injecting drug users. Reference strains were labeled using the HIV databases ID, which include a two letter code indicating the country of origin (<a href="http://www.hiv.lanl.gov/" target="_blank">http://www.hiv.lanl.gov/</a>).</p

Demographic details of HIV gag PCR positive participants.

<p>The frequencies of all values are given in parentheses.</p

Phylogenetic analysis of HIV transmission between IDUs, MSM, and MSM families.

<p>The studied population sequences were compared to the IDU sequences obtained from a previous study, which are highlighted in black. The 47 strains from MSM and M-IDU (highlighted) are shown in blue, 15 MSM spouses (MS-) are shown in green and 14 MSM children (MC-) are shown in red. Members of each family are assigned by similar digit label following the letter prefix. The numbers along the monophyletic branches correspond to bootstrap values. Branch lengths in nucleotide substitutions per site were scaled according to the bar at the bottom of the tree.</p