Tipifarnib Potentiates the Antitumor Effects of PI3Kα Inhibition in PIK3CA- and HRAS-Dysregulated HNSCC via Convergent Inhibition of mTOR Activity.

Unlabelled: Outcomes for patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) are poor, with median overall survival (OS) ranging from 6 to 18 months. For those who progress on standard-of-care (chemo)immunotherapy, treatment options are limited, necessitating the development of rational therapeutic strategies. Toward this end, we targeted the key HNSCC drivers PI3K-mTOR and HRAS via the combination of tipifarnib, a farnesyltransferase (FTase) inhibitor, and alpelisib, a PI3Kα inhibitor, in multiple molecularly defined subsets of HNSCC.

A prospective randomized comparative study to evaluate the effect of palliative hypo-fractionated radiotherapy with concurrent chemotherapy versus hypo-fractionated radiotherapy alone in advanced and unresectable head and neck cancer with no metastasis.

Introduction: A short duration, palliative radiotherapy schedule for locally advanced and unresectable head and neck cancer (LAUHNC) was evaluated in terms of palliation of cancer-related symptoms and acute toxicities.

Aims And Objectives: The aim of the study was to compare the role and feasibility of hypo-fractionated radiotherapy with concurrent chemotherapy and hypo-fractionated radiotherapy in LAUHNC.

Materials And Methods: All the patients included in this study of LAUHNC were not fit for curative treatment.

Mutant KRAS regulates transposable element RNA and innate immunity via KRAB zinc-finger genes.

RAS genes are the most frequently mutated oncogenes in cancer, yet the effects of oncogenic RAS signaling on the noncoding transcriptome remain unclear. We analyzed the transcriptomes of human airway and bronchial epithelial cells transformed with mutant KRAS to define the landscape of KRAS-regulated noncoding RNAs. We find that oncogenic KRAS signaling upregulates noncoding transcripts throughout the genome, many of which arise from transposable elements (TEs).

CXCL12 in Pancreatic Cancer: Its Function and Potential as a Therapeutic Drug Target.

Pancreatic ductal adenocarcinoma (PDAC) is a disease with limited therapeutic options and dismal long-term survival. The unique tumor environment of PDAC, consisting of desmoplastic stroma, immune suppressive cells, and activated fibroblasts, contributes to its resistance to therapy. Activated fibroblasts (cancer-associated fibroblasts and pancreatic stellate cells) secrete chemokines and growth factors that support PDAC growth, spread, chemoresistance, and immune evasion.

Potential of Farnesyl Transferase Inhibitors in Combination Regimens in Squamous Cell Carcinomas.

Current therapies for recurrent and metastatic SCC are associated with poor outcomes, and options for later lines of treatment are limited. Insights into potential therapeutic targets, as well as mechanisms of resistance to available therapies, have begun to be elucidated, creating the basis for exploration of combination approaches to drive better patient outcomes. Tipifarnib, a farnesyl transferase inhibitor (FTI), is a small molecule drug that has demonstrated encouraging clinical activity in a genetically-defined subset of head and neck squamous cell carcinoma (HNSCC)-specifically, tumors that express a mutation in the protooncogene.

Clinical Profile of Indian Children with Down Syndrome.

This retrospective study was performed on 208 patients with Down syndrome (DS) from heterogeneous ethnic population and admitted under Genetics Metabolic Unit. The aim of the study was to look for phenotypic variability and associated complications in children and adolescents with DS. The average age of the evaluated DS patients was 34 months.

Histomorphological and Morphometric Evaluation of Microvessel Density in Nodal Non-Hodgkin Lymphoma Using CD34 and CD105.

 Expression of angiogenic markers determined by microvessel density (MVD) could be used as a reliable predictor of prognosis and as a potential target for antiangiogenic therapy in different categories of non-Hodgkin lymphoma (NHL).  The aim of this study was to evaluate MVD using immunohistochemical methods and computer-assisted quantitative image analysis in nodal NHL patients and compare CD34 and CD105 expression in lymph nodes of NHL patients.  The present study was conducted on 60 lymph node biopsies received in the Department of Pathology at our tertiary care center for histopathological examination.

Evolution of a guarded decoy protease and its receptor in solanaceous plants.

Rcr3 is a secreted protease of tomato that is targeted by fungal effector Avr2, a secreted protease inhibitor of the fungal pathogen Cladosporium fulvum. The Avr2-Rcr3 complex is recognized by receptor-like protein Cf-2, triggering hypersensitive cell death (HR) and disease resistance. Avr2 also targets Rcr3 paralog Pip1, which is not required for Avr2 recognition but contributes to basal resistance.

A non-canonical BRD9-containing BAF chromatin remodeling complex regulates naive pluripotency in mouse embryonic stem cells.

The role of individual subunits in the targeting and function of the mammalian BRG1-associated factors (BAF) complex in embryonic stem cell (ESC) pluripotency maintenance has not yet been elucidated. Here we find that the Bromodomain containing protein 9 (BRD9) and Glioma tumor suppressor candidate region gene 1 (GLTSCR1) or its paralog GLTSCR1-like (GLTSCR1L) define a smaller, non-canonical BAF complex (GBAF complex) in mouse ESCs that is distinct from the canonical ESC BAF complex (esBAF). GBAF and esBAF complexes are targeted to different genomic features, with GBAF co-localizing with key regulators of naive pluripotency, which is consistent with its specific function in maintaining naive pluripotency gene expression.

PDX1 dynamically regulates pancreatic ductal adenocarcinoma initiation and maintenance.

Aberrant activation of embryonic signaling pathways is frequent in pancreatic ductal adenocarcinoma (PDA), making developmental regulators therapeutically attractive. Here we demonstrate diverse functions for pancreatic and duodenal homeobox 1 (PDX1), a transcription factor indispensable for pancreas development, in the progression from normal exocrine cells to metastatic PDA. We identify a critical role for PDX1 in maintaining acinar cell identity, thus resisting the formation of pancreatic intraepithelial neoplasia (PanIN)-derived PDA.

Primary breast mucormycosis: FNAC diagnosis of a rare entity.

Mucormycosis is the common name given to several different diseases caused by fungi in the order of mucorales. The clinical hallmark of these opportunistic pathogens in invasive mucormycosis is tissue necrosis resulting from angioinvasion and subsequent thrombosis. Rarely the disease may affect immunocompetent individuals.

SIRT7 inactivation reverses metastatic phenotypes in epithelial and mesenchymal tumors.

Metastasis is responsible for over 90% of cancer-associated mortality. In epithelial carcinomas, a key process in metastatic progression is the epigenetic reprogramming of an epithelial-to-mesenchymal transition-like (EMT) change towards invasive cellular phenotypes. In non-epithelial cancers, different mechanisms must underlie metastatic change, but relatively little is known about the factors involved.

Role of morphometry and proliferative parameters in grading of urothelial neoplasms.

Introduction: Mean nuclear area of 10 nuclei (MNA-10), mitotic activity index (MAI) and Ki-67 are highly reproducible and can be routinely used as adjuncts to histopathological grading in classifying tumors. Assays of these biomarkers are non-invasive, rapid, easy to perform, more objective and accurate, with high sensitivity and specificity, and correlate well with tumor grade.

Material And Methods: This study was conducted at the Department of Pathology PGIMS, Rohtak on 50 cases, of which 25 cases were high-grade, 15 low-grade, 6 Papillary Urothelial Neoplasm of Low Malignant Potentialand 4 reactive lesions as per the 2004 ISUP/WHO classification.

Brg1 promotes both tumor-suppressive and oncogenic activities at distinct stages of pancreatic cancer formation.

Pancreatic ductal adenocarcinoma (PDA) develops predominantly through pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasm (IPMN) precursor lesions. Pancreatic acinar cells are reprogrammed to a "ductal-like" state during PanIN-PDA formation. Here, we demonstrate a parallel mechanism operative in mature duct cells during which functional cells undergo "ductal retrogression" to form IPMN-PDA.

Regulation of active genome integrity and expression by Rad26p.

Rad26p is a SWI/SNF-like ATPase in yeast, and is conserved among eukaryotes. Both Rad26p and its human homolog CSB (Cockayne syndrome group B) are involved in regulation of chromatin structure, transcription and DNA repair.  Thus, mutations or malfunctions of these proteins have significant effects on cellular functions.

Brunner gland hamartoma masquerading as malignancy; a rare case report.

Brunner's gland hamartoma is a rare benign tumour of the duodenum. It was first described by Cruveilhier in 1835. Presently around 200 cases have been reported in literature.

Rrd1p, an RNA polymerase II-specific prolyl isomerase and activator of phosphoprotein phosphatase, promotes transcription independently of rapamycin response.

Rrd1p (resistance to rapamycin deletion 1) has been previously implicated in controlling transcription of rapamycin-regulated genes in response to rapamycin treatment. Intriguingly, we show here that Rrd1p associates with the coding sequence of a galactose-inducible and rapamycin non-responsive GAL1 gene, and promotes the association of RNA polymerase II with GAL1 in the absence of rapamycin treatment following transcriptional induction. Consistently, nucleosomal disassembly at GAL1 is impaired in the absence of Rrd1p, and GAL1 transcription is reduced in the Δrrd1 strain.

Mechanisms of antisense transcription initiation from the 3' end of the GAL10 coding sequence in vivo.

In spite of the important regulatory functions of antisense transcripts in gene expression, it remains unknown how antisense transcription is initiated. Recent studies implicated RNA polymerase II in initiation of antisense transcription. However, how RNA polymerase II is targeted to initiate antisense transcription has not been elucidated.

Rad26p, a transcription-coupled repair factor, promotes the eviction and prevents the reassociation of histone H2A-H2B dimer during transcriptional elongation in vivo.

We have recently demonstrated the formation of an atypical histone H2A-H2B dimer-enriched chromatin at the coding sequence of the active gene in the absence of Rad26p in vivo. However, the mechanisms for such a surprising observation remain unknown. Here, using a ChIP assay, we demonstrate that Rad26p promotes the eviction of histone H2A-H2B dimer and prevents the reassociation of the dimer with naked DNA in the wake of elongating RNA polymerase II at the coding sequence of the active GAL1 gene.

Rad26p regulates the occupancy of histone H2A-H2B dimer at the active genes in vivo.

Recently, we have demonstrated a predominant association of Rad26p with the coding sequences but not promoters of several GAL genes following transcriptional induction. Here, we show that the occupancy of histone H2A-H2B dimer at the coding sequences of these genes is not altered following transcriptional induction in the absence of Rad26p. A histone H2A-H2B dimer-enriched chromatin in Δrad26 is correlated to decreased association of RNA polymerase II with the active coding sequences (and hence transcription).

The 19S proteasome subcomplex promotes the targeting of NuA4 HAT to the promoters of ribosomal protein genes to facilitate the recruitment of TFIID for transcriptional initiation in vivo.

Previous studies have implicated SAGA (Spt-Ada-Gcn5-acetyltransferase) and TFIID (Transcription factor-IID)-dependent mechanisms of transcriptional activation in yeast. SAGA-dependent transcriptional activation is further regulated by the 19S proteasome subcomplex. However, the role of the 19S proteasome subcomplex in transcriptional activation of the TFIID-dependent genes has not been elucidated.

Regulation of chromatin assembly/disassembly by Rtt109p, a histone H3 Lys56-specific acetyltransferase, in vivo.

Rtt109p, a histone acetyltransferase, associates with active genes and acetylates lysine 56 on histone H3 in Saccharomyces cerevisiae. However, the functional role of Rtt109p or H3 Lys(56) acetylation in chromatin assembly/disassembly (and hence gene expression) immediately switching transcription on or off has not been clearly elucidated in vivo. Here, we show that Rtt109p promotes the eviction of histone H3 from a fast inducible yeast gene, GAL1, following transcriptional initiation via histone H3 Lys(56) acetylation.