Analysis of mutational variations in TP53 tumour suppressor gene among Pakistani head and neck cancer patients.

The aim of this study was to determine the frequency of TP53 mutation among Pakistani head and neck cancer (HNC) patients who visited Nishtar Hospital Multan and Nishtar Institute of Dentistry (NID), Multan, Pakistan. While significant research has been conducted on the role of p53 in HNC throughout the world, this study is the first of its kind in Southern Punjab, Pakistan. A total of 242 samples (121 cases and 121 controls) were collected from Nishtar Hospital Multan and NID, Multan, Pakistan. After histopathological analysis to determine the stage type and grade of malignancy, DNA extraction and sequencing were carried out to assess any mutations in the TP53 region (exons 5-8). Genetic screening was performed by the polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) technique and Chromas 2.6.6 was used to visualise the sequencing results. The mean age of cases was 50.73 ±16.41 years and controls were 37.55 ± 15.51 years. The frequency of HNC was higher in male patients (65.28%) than in female patients (34.71%). Overall, this cancer was found to be significantly more prevalent in the age group of >35-55 years (p < 0.001). Smoking (51% versus 14%), naswar usage (15.7% versus 6.6%), poor oral hygiene (52.9% versus 29.8%) and anemic status (57.0% versus 4.1%) were significantly associated with cases (p ≤ 0.05) compared to controls. Only 04 samples exon 5 (1 sample), exon 7 (2 samples) and exon 8 (1 sample) with changed mobility patterns were found on the SSCP gel. All mutations were missense and heterozygous. Out of four mutant samples, three mutations were in the hotspot regions (codon 175, 245 and 248) of p53. Based on this study, there may be a weak association between the TP53 exon 5-8 mutation and HNC patients in Southern Punjab, Pakistan.

Golgi organization is regulated by proteasomal degradation.

The Golgi is a dynamic organelle whose correct assembly is crucial for cellular homeostasis. Perturbations in Golgi structure are associated with numerous disorders from neurodegeneration to cancer. However, whether and how dispersal of the Golgi apparatus is actively regulated under stress, and the consequences of Golgi dispersal, remain unknown. Here we demonstrate that 26S proteasomes are associated with the cytosolic surface of Golgi membranes to facilitate Golgi Apparatus-Related Degradation (GARD) and degradation of GM130 in response to Golgi stress. The degradation of GM130 is dependent on p97/VCP and 26S proteasomes, and required for Golgi dispersal. Finally, we show that perturbation of Golgi homeostasis induces cell death of multiple myeloma in vitro and in vivo, offering a therapeutic strategy for this malignancy. Taken together, this work reveals a mechanism of Golgi-localized proteasomal degradation, providing a functional link between proteostasis control and Golgi architecture, which may be critical in various secretion-related pathologies.

One-Pot Synthesis and Evaluation of Antileishmanial Activities of Functionalized S-Alkyl/Aryl Benzothiazole-2-carbothioate Scaffold.

The synthesis of hitherto unreported S-alkyl/aryl benzothiazole-2-carbothioate is reported from thiols, oxalyl chloride, and 2-aminothiophenols using 10 mol % n-tetrabutylammonium iodide (TBAI) as catalyst in acetonitrile through multicomponent reaction (MCR) strategy. The present protocol favored formation of benzothiazoles and thioesters via simultaneous formation of C-N and C-S bonds in good yields with a wide range of substrates. A few of the synthesized derivatives were evaluated for their antimicrobial activity against the protozoan parasite Leishmania donovani, a causative agent of visceral leishmaniasis (VL). Further, these compounds displayed no toxicity toward macrophage RAW 264.7 cells and are therefore nontoxic and effective antileishmanial leads. In silico docking studies were performed to understand the possible binding site interaction with trypanothione reductase (TryR).