Search

Germline mutations in BRCA1 and BRCA2 (BRCA1/2) genes considerably increase breast and ovarian cancer risk. Given that tumors with these mutations have elevated genomic instability, they exhibit relative vulnerability to certain chemotherapies and targeted treatments based on poly (ADP-ribose) polymerase (PARP) inhibition. However, the molecular mechanisms that influence cancer risk and therapeutic benefit or resistance remain only partially understood. BRCA1 and BRCA2 have also been implicated in the suppression of R-loops, triple-stranded nucleic acid structures composed of a DNA:RNA hybrid and a displaced ssDNA strand. Here, we report that loss of RNF168, an E3 ubiquitin ligase and DNA double-strand break (DSB) responder, remarkably protected Brcol-mutant mice against mammary tumorigenesis. We demonstrate that RNF168 deficiency resulted in accumulation of R-loops in BRCA1/2-mutant breast and ovarian cancer cells, leading to DSBs, senescence, and subsequent cell death. Using interactome assays, we identified RNF168 interaction with DHX9, a helicase involved in the resolution and removal of R-loops. Mechanistically, RNF168 directly ubiquitylated DHX9 to facilitate its recruitment to R-loop-prone genomic loci. Consequently, loss of RNF168 impaired DHX9 recruitment to R-loops, thereby abrogating its ability to resolve R-loops. The data presented in this study highlight a dependence of BRCA1/2-defective tumors on factors that suppress R-loops and reveal a fundamental RNF168-mediated molecular mechanism that governs cancer development and vulnerability., Introduction Germline-deleterious mutations in BRCA1 and BRCA2 (BRCA1/2) predispose to high lifetime risks of breast and ovarian cancer (1). BRCA1/2 are essential for DNA double-strand break (DSB) repair through homologous [...]

Background: Bone Marrow examination is considered to be the most indispensable diagnostic tool for the evaluation of many neoplastic and non-neoplastic haematological disorders. After an initial assessment of suspicious cases on abnormal laboratory parameters along with the clinical presentation of the patient marrow examination is finally required for diagnosis as well as management of many haematological malignancies as it offers a clear cytological as well as histological picture of Bone Marrow aspirate and biopsy respectively. The Objective was to evaluate the significance of Bone Marrow examination in patients with abnormal haematological parameters. Methods: A retrospective study conducted at the Pathology Department of Pak Emirates Military Hospital from (Jan-June 2022) On data from150 patients who were advised to undergo bone marrow examination due to abnormal lab parameters and peripheral smear findings after informed consent and approval from the ethics review committee, to find out the correlation of abnormal haematological parameters and aspirate findings which have led to a definitive diagnosis. Data comprising basic demographic variables (age, gender etc.), Abnormal Haematological Parameters (CBC), peripheral smear findings and Aspirate findings were analyzed using SPSS version 23.0.Results: Out of 150 studied participants with abnormal haematological parameters 24 (16%) were diagnosed on bone marrow examination as acute leukaemia / Hodgkin's and Non-Hodgkin's lymphoma respectively, 13 (9%) cases of aplastic anaemia and Autoimmune HaemolyticAnaemia, 33 (22%)cases of hypersplenism, CML and multiple myeloma. While 22 (15%) cases were diagnosed with BME as CKD and reactive changes. Moreover, 22(15%) cases were found to have Iron Deficiency anaemia respectively. Conclusion: The study revealed that patients with abnormal haematological parameters should undergo bone marrow examination to ascertain the diagnosis for malignant as well as non-malignant conditions that could cause abnormal lab parameters. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the performance of two different cell separators used for plateletpheresis at our facility. This evaluation was done to ascertain which cell separator performed better in terms of various product parameters. Study Design: Cross Sectional study. Setting: National Hospital, Lahore. Period: July to December 2020. Material & Methods: A total of 100 plateletapheresis procedures were done, 50 on Cobe Spectra and 50 on Haemonetics MCS900. Male donors were selected after detailed medical history, screening and informed consent. For each cell separator, the total procedure time, collection rate and platelet yield of the final product (single donor platelets) was noted and compared. The predonation platelet count of each donor was also recorded. Results: Donor turnaround time was better for the Cobe 60.1 + 2.757 min vs 81.1 + 3.311 min on Heamonetics (p value < 0.0001). Cobe had a superior collection rate 0.065+0.0088 (PLTÃ--10 11/min) than Heamonetics 0.0519 + 0.007 (PLTÃ--10 11/min) (p value< 0.0001). For both cell separators, the final product was similar in terms of platelet yield (p value = 0.56). Overall, donor predonation platelet counts ranged from 220-480x109/L. Pearson correlation test showed positive correlation (r = 0811, p value; < 0.0001) between platelet yield and donor platelet count. Conclusion: Continuous flow cell separators, like the Cobe spectra, offer a high quality platelet product with greater efficiency when compared to intermittent flow cell separators like the Haemonetics. [ABSTRACT FROM AUTHOR]

The traditional medicinal mushroom Hericium erinaceus is known for enhancing peripheral nerve regeneration through targeting nerve growth factor (NGF) neurotrophic activity. Here, we purified and identified biologically new active compounds from H. erinaceus, based on their ability to promote neurite outgrowth in hippocampal neurons. N‐de phenylethyl isohericerin (NDPIH), an isoindoline compound from this mushroom, together with its hydrophobic derivative hericene A, were highly potent in promoting extensive axon outgrowth and neurite branching in cultured hippocampal neurons even in the absence of serum, demonstrating potent neurotrophic activity. Pharmacological inhibition of tropomyosin receptor kinase B (TrkB) by ANA‐12 only partly prevented the NDPIH‐induced neurotrophic activity, suggesting a potential link with BDNF signaling. However, we found that NDPIH activated ERK1/2 signaling in the absence of TrkB in HEK‐293T cells, an effect that was not sensitive to ANA‐12 in the presence of TrkB. Our results demonstrate that NDPIH acts via a complementary neurotrophic pathway independent of TrkB with converging downstream ERK1/2 activation. Mice fed with H. erinaceus crude extract and hericene A also exhibited increased neurotrophin expression and downstream signaling, resulting in significantly enhanced hippocampal memory. Hericene A therefore acts through a novel pan‐neurotrophic signaling pathway, leading to improved cognitive performance. [ABSTRACT FROM AUTHOR]

The 21st century, the understanding of technology's use and significance has grown. In education, the traditional method of teaching is being replaced by technology. Despite several studies documenting that subtitled videos help language learners, there is a clear lack of research done in this area, especially in Pakistani context. This study examined how subtitled videos affect ESL learners' listening comprehension and vocabulary learning. Opting for a quasi-experimental study, researchers took a pre-test, post-test, and attitude questionnaire to gather qualitative and quantitative data on the groups. Using the paired t-test, the researchers found out that the two-tailed significance value of the pre-test of both the group's listening comprehension lied at .948 and vocabulary's results lied at .876, both p-values higher than 0.05, thus proving that the group's listening and vocabulary skills were on the same level. However, the post-test of listening comprehension lied at 0.07 and vocabulary learning lied at 0.14, both p-values lesser than 0.05. Adding on, the researchers also opted for descriptive statistics and participants questionnaire, through which they found that the experimental group improved in listening comprehension and vocabulary learning compared to the control group, proving the alternative hypothesis. The present research provides significant qualitative and quantitative data for increasing awareness about modern teaching methods and the possibilities of adjustments by policymakers, syllabus designers, and educators. This research can also aid future researchers in further exploration of this topic on a deeper level so to better understand the importance of appropriate inclusivity of technology into education. [ABSTRACT FROM AUTHOR]

The newly identified tripartite motif (TRIM) family of proteins mediate innate immunity and other critical cellular functions. Here we show that TRIM21, which mediates the autoimmune diseases rheumatoid arthritis, systemic lupus erythematosus, and Sjogren's syndrome, is a previously undescribed lgG receptor with a binding mechanism unlike known mammalian Fc[gamma], receptors. TRIM21 simultaneously targets conserved hot-spot residues on both lg domains of the Fc fragment using a PRYSPRY domain with a preformed multisite interface. The binding sites on both TRIM21 and Fc are highly conserved to the extent that the proteins are functionally interchangeable through murine, canine, primate, and human species. Pre-steady-state analysis exposes mechanistic conservation at the level of individual residues, which make the same energetic and kinetic contributions to binding despite varying in sequence. Together, our results reveal that TRIM21 is a previously undescribed type of lgG receptor based on a non-lg scaffold whose interaction at the fundamental level--structural, thermodynamic, and kinetic--is evolutionarily conserved. PRYSPRY | systemic lupus erythematosus | TRIM5[alpha] | Ro52