Is Training Working Memory in Children with Learning Disabilities a Viable Solution? A Systematic Review.

Background: Working memory (WM) is one of the most influential cognitive functions in encoding, registering, and retrieving information. It influences the learning process in children. Its role becomes essential, especially in a child with a learning disability (LD). Researchers worldwide are giving much prominence to WM, especially in devising cognitive retraining strategies for better cognitive functioning and academic attainment in these children. This current study aims to explore globally used instruments to measure this construct and review effective WM training models in the cognitive rehabilitation of children with LD. This study used a systematic review, availing the elaborate "Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA)" guidelines. Summary: The databases of Google Scholar, PubMed, and Web of Science were searched thoroughly, and those studies, which met the inclusion criteria, were considered for this review. Out of 770 studies found with keywords, only six met the inclusion criteria and were selected for a detailed analysis. The outcome of the current review provides trustworthy evidence of poor performance, especially in tasks involving verbal and executive WM in children with all types of learning disabilities (LD) and difficulties. The studies reviewed support the hypothesis that WM can improve with training and significantly improve children's academic attainment. Key Message: Further this review recommends that research and efforts must go into devising these cognitive training techniques. Children have high cerebral plasticity; hence, using cognitive training (emphasizing WM training and other cognitive functions) with them would enhance their cognitive functioning and capacity, improving their academic performance.

Low-grade malt lymphoma of the nasopharynx in young adults: Successful treatment of a rare diagnosis at a rare site by radiotherapy.

INTRODUCTION: Mucosa Associated Lymphoid Tissue (MALT) lymphoma is the third most common subgroup of Non-Hodgkin's lymphoma and is the most common type of primary extranodal lymphoma. They are rarely found in the nasopharyngeal region and their mean age at presentation is the sixth decade of life. MATERIALS AND METHODS: We present the clinical, pathological, treatment and 5-year follow-up data of 5 cases of nasopharyngeal MALT lymphoma treated with definitive radiotherapy at our hospital, between 2009 and 2011. RESULTS: The average age of diagnosis was 27 years which is more than a decade earlier than what has been reported previously. Clinical symptoms included nasal obstruction, tinnitus and hearing loss. All five patients had locoregional disease. They were treated by definitive radiotherapy to a dose between 30 to 40 Gy. At 5 years of follow-up, 4 patients were in complete remission while one had disease relapse. CONCLUSION: The younger age of presentation compared to older reports in this rare subsite was an interesting finding in our study. The authors speculate that rising levels of particulate air pollution may have played a part in the etiology in this younger population. Our series shows that despite the younger age, the disease displays an indolent course and responds well to radiotherapy alone as the primary treatment. Recurrence or disseminated disease is also highly treatable with systemic chemotherapy.

An Audit of Diagnostic Disparity between Intraoperative Frozen Section Diagnosis and Final Histopathological Diagnosis of Central Nervous System Lesions at a Tertiary Care Center.

Introduction Evaluation of intraoperative squash smear and frozen section (FS) in central nervous system (CNS) neoplasms is consistently practiced for rapid assessment and has several advantages to its credence. It is an invaluable tool to ensure adequacy of tissue obtained to establish the diagnosis. Moreover, it aids in guiding the surgeon for critical decisions regarding the extent of resection. Although molecular markers have been integrated with morphology in the revised 2016 World Health Organization classification of brain tumors, precise morphological assessment still remains the foundation for the diagnosis and rapid intraoperative assessment of morphological details is equally critical and rewarding. Objective This study aims to audit the diagnostic disparity between intraoperative diagnoses based on a combination of squash cytology and FS in cases of CNS lesions with gold standard, final diagnosis based on examination of formalin fixed paraffin embedded hematoxylin, and eosin-stained tissue sections. Materials and Methods All intraoperative squash cytology and FS reported for CNS lesions from January 2017 to December 2020 were reviewed. The cases were categorized into three groups-group 1: when diagnosis of intraoperative diagnosis based on a combination of squash cytology and FS was same as the final histopathological diagnosis (concordant), group 2: partially concordant, and group 3: discordant cases. Statistical Analysis Descriptive statistics was used to classify the data and diagnostic accuracy was calculated. Results Complete concordance was present in 69.96% (191/273) cases, 20.1% (55/273) cases showed partial concordance, and 9.89% (27/273) cases were discordant with histopathological diagnosis. Out of the 27 discordant cases, misclassification of tumor type was the most common category (11 cases, 40%), followed by grading mismatch (7 cases, 25.9%), and misdiagnosis of tumor versus nontumor conditions (9 cases, 33.3%). Conclusion Our study shows that combination of intraoperative squash cytology and FS shows a high percentage of accuracy in arriving at intraoperative diagnosis in cases of intracranial lesions. Regular audits of discordant cases should be conducted by surgeons and pathologists as part of a quality assurance measure to sensitize themselves with the potential pitfalls, minimizing misinterpretation and helping in providing a more conclusive opinion to the operating surgeons.

Determining PD-L1 expression in head and neck squamous cell carcinoma using immunohistochemistry.

Background: Advanced head and neck squamous cell carcinoma (HNSCC) has limited treatment options. Programmed death-ligand1 (PD-L1) expressed by tumor cells interacts with PD-1 receptor on T lymphocytes leading to immune evasive response and survival advantage. Therapy with immune check-point inhibitors target PD-1/PD-L1 blockade inducing tumor regression. Immunohistochemistry (IHC) for PD-L1 expression enables patient selection for immunotherapy and may be considered a potential predictor of clinical response. Methods: A retrospective analysis of IHC for PD-L1 expression using manual laboratory developed technique (LDT) with antibody clone 22C3 (Dako) in 93 cases of HNSCC. PD-L1 expression was correlated with age, gender, tumor site, grade and stage. Results: PD-L1 IHC was performed in 93 cases and immunopositivity was noted in 59 (63.4%) cases. High expression with combined proportion score (CPS) ≥50 was seen in 15 (16.1%) cases and low expression with CPS ≥1 expression was seen in 44 (47.3%) cases. An almost-perfect interobserver agreement was noted by two pathologists for PD-L1 IHC expression (Cohen's kappa coefficient = 0.910). No statistically significant correlation was noted between PD-L1 score and patient demographics, tumor site, grade or stage. Conclusion: Detection of PD-L1 status by IHC enables identification of HNSCC patients eligible for future targeted immunotherapy.

Application of International association for the study of lung cancer/American Thoracic Society/European Respiratory Society criteria for the diagnosis of lung carcinomas on small biopsies: A tertiary care center experience.

BACKGROUND: The new IASLC/ATS/ERS classification provides standardized terminology for lung cancer diagnosis in small biopsies and cytology specimens. OBJECTIVES: The aim was to study the feasibility of the guidelines using one marker for adenocarcinoma (ADC) and one for squamous cell carcinoma (SQCC) in non-small cell lung carcinomas (NSCLCs). SUBJECT AND METHODS: In this study, we reviewed all the formalin-fixed paraffin-embedded tissue blocks diagnosed as lung carcinoma between July 2016 and December 2017. Cases were labeled as SCLC, ADC, SQCC, NSCLC favor ADC, NSCLC favor SQCC, NSCLC-not otherwise specified (NOS), and NSCLC-NOS possible adeno-SQCC (ADSQCC) as per IASLC/ATS/ERS 2011 guidelines. A three-step approach incorporating morphology, immunohistochemistry (IHC), and molecular analysis was used. RESULTS: One hundred and nine cases were included. Six of the 109 cases were SCLC and 1 case was of large-cell neuroendocrine type. Of the remaining 102, 51 were diagnosed based on their classical histomorphology into SQCC (8) and ADC (43). Remaining 51 cases required IHC/special stains for categorization. The panel comprised anti-CK7, anti-thyroid transcription factor-1 (TTF-1), and anti-p63. Twenty-nine were positive for anti-TTF-1 and thus labeled as NSCLC favor ADC. Fifteen were labeled as NSCLC favor SQCC as they were highlighted by anti-p63. Four cases showed reaction to both the antibodies in different sets of tumor cells and thus were classified as NSCLC-NOS, possible ADSQCC. Remaining 3 cases did not show reaction to any of the antibodies and hence were labeled NSCLC-NOS. CONCLUSION: The need for every laboratory to use minimal tissue for ancillary tests to diagnose lung carcinoma on small biopsies is reemphasized. Tissue from small biopsies needs to be preserved not only for the diagnosis but also for molecular testing and evaluation of markers of resistance to therapy, in this era of personalized medicine.

Using positron-emission tomography-computed tomography for predicting radiotherapy-induced tumor regression in carcinoma esophagus in an Indian population.

Carcinoma esophagus is a common malignancy of the Indian subcontinent. The role of positron-emission tomography-computed tomography (PET-CT) in the assessment of response to radiotherapy has been widely studied and accepted. However, its precise use as a predictive tool for actual histopathological response to radiotherapy needs further evaluation, especially in an Indian population. The aim of this study was to identify a quantum of metabolic response on PET-CT that can also predict for a good pathological response. Forty-four patients of carcinoma esophagus treated with neoadjuvant chemoradiotherapy followed by surgery were included in the study. All patients underwent a PET-CT before starting treatment as well as at 4-6 weeks after completion of radiotherapy. The percentage change in pre and posttreatment maximum standardized uptake value (SUVmax) value (ΔSUV%) of the primary tumor was correlated against histopathological tumor regression grade (TRG) as per the Mandard's system. Seventy-five percent of the patients with a significant metabolic response, i.e., a ΔSUV% of 60% or more, also had a good pathological response to treatment. Thus, by considering a ΔSUV% of 60%, we could predict for a good pathological response (TRG of 1 or 2) to chemoradiotherapy in our patient set with a sensitivity of 95.45% and a specificity of 72.72%.

Upfront Skeletal Muscle Metastases from Non-small Cell Lung Carcinoma: Report of an Extremely Rare Occurrence Detected by 18F-Fluorodeoxyglucose Positron Emission Computed Tomography Scan.

Adenocarcinoma lung with upfront metastases to skeletal muscle is rarely encountered in clinical practice since skeletal muscles are highly resistant to dissemination from solid organs. Moreover, these muscle metastatic lesions generally present with pain and palpable mass to get detected clinically. However, silent skeletal muscle metastases without any symptoms or signs getting detected by functional imaging with whole body 18F-fluorodeoxyglucose positron emission/computed tomography (18FDG-PET/CT) scan have been scarcely described in literature, while we present such an interesting case in a 45-year-old female. She was diagnosed as a case of biopsy-proven metastatic adenocarcinoma lung after evaluation by 18FDG-PET/CT. Despite treatment with palliative chemoradiotherapy, her disease progressed, and she finally succumbed to her illness. This case is discussed to highlight an unusual scenario we encountered, the clinical course of the disease with its management and overall poor prognosis.

Molecular mechanisms of anti-tumor properties of P276-00 in head and neck squamous cell carcinoma.

BACKGROUND: Tumors of the head and neck present aggressive pathological behavior in patients due to high expression of CDK/CCND1 proteins. P276-00, a novel CDK inhibitor currently being tested in clinic, inhibits growth of several cancers in vitro and in vivo. The pre clinical activity of P276-00 in head and neck cancer and its potential mechanisms of action at molecular level are the focus of the current studies. METHOD: We have investigated the anti-cancer activity of P276-00 in head and neck tumors in vitro and in vivo. Candidate gene expression profiling and cell based proteomic approaches were taken to understand the pathways affected by P276-00 treatment. RESULTS: It was observed that P276-00 is cytotoxic across various HNSCC cell lines with an IC50 ranging from 1.0-1.5 µmoles/L and culminated in significant cell-cycle arrest in G1/S phase followed by apoptosis. P276-00 treatment suppressed cell proliferation through inhibition of CCND1 expression, reduced phosphorylation of retinoblastoma protein and abrogative transcription of E2F1 gene targets. Further, we observed that apoptosis was mediated through P53 activation leading to higher BAX/BCL-2 ratio and cleaved caspase-3 levels. It was also seen that P276-00 treatment reduced expression of tumor micro-environment proteins such as IL-6, secreted EGFR and HSPA8. Finally, P276-00 treatment resulted in significant tumor growth inhibition in xenograft tumor models via lowered proliferative activity of E2F1 and aggravated P53 mediated apoptosis. CONCLUSION: In summary, we have observed that P276-00 inhibits cyclin-D/CDK4/P16/pRB/E2F axis and induces apoptosis by increased P53 phosphorylation in HNSCC cells. These results suggest a novel indication for P276-00 in head and neck cancer with a potential role for IL-6 and HSPA8 as candidate serum biomarkers.

NF-κB dependent anti-inflammatory activity of chlorojanerin isolated from Saussurea heteromalla.

Medicinal plants have shown great promise as a source of novel drug compounds for the treatment of inflammatory disorders. In our search for new entities with anti-inflammatory potential, the extracts of the whole plant of Saussurea heteromalla (family-Asteraceae), collected from Himalayas, were evaluated in the high throughput screen for TNF-α and IL-6 inhibitors. The extract blocked TNF-α and IL-6 production in LPS stimulated THP-1 cells (human acute monocyte leukemia cell line) completely at 10 and 30 µg/ml. The plant has been found as a new source of chlorojanerin, a guaianolide type of sesquiterpene lactone. Chlorojanerin was shown to be significantly effective in inhibiting TNF-α and IL-6 production in LPS-stimulated THP-1 cells (IC(50)=2.3±0.2 µM and 1.8±0.7 µM respectively). The compound also blocked TNF-α and IL-6 production from LPS-stimulated human monocytes (IC(50)=1.5±0.4 and 0.7±0.2 µM respectively) and synovial cells from a patient with rheumatoid arthritis (IC(50)<0.03 and 0.5 µM respectively). Transcriptional profiling of the LPS stimulated THP-1 cells revealed that chlorojanerin exerted its anti-inflammatory effect by inhibiting the expression of 8 genes involved in activating the transcription factor - NF-κB. Real time analysis of these genes validated the effect of chlorojanerin on the classical downstream targets of NF-κB. Thus, this study clearly delineated 8 genes which were specifically mitigated due to the effect of chlorojanerin on NF-κB induced signaling at the mRNA level. Further, chlorojanerin at 5 µM also inhibited the binding of NF-κB in a GFP reporter assay system by 55.5% thus validating the microarray gene expression data. This work is a step towards the isolation and characterization of lead anti-inflammatory agents from the extract of Saussurea heteromalla, which can be developed into better therapeutic molecules targeted towards some specific inflammatory diseases.

Antitumor activity of NPB001-05, an orally active inhibitor of Bcr-Abl tyrosine kinase.

Scientists are constantly searching for phytochemical compounds with anti-cancer activity. In this study, activity of plant extract NPB001-05 from Piper betle was tested on human chronic myelogenous leukemia (CML) xenograft models. NPB001-05 was active when dosed orally (500 mg/kg) once or twice a day in xenograft tumor models. NPB001-05 showed activity to T315I tumor xenograft, where imatinib failed to show antitumor activity. NPB001-05 showed no relevant toxicity in animal models during 2 weeks exposure to drug. Responsive tumor showed inhibition of tyrosine kinase activity with lowered Bcr-Abl protein levels and increased apoptosis. Microarray based transcription profiling studies demonstrated that both imatinib and NPB001-05 dysregulated imatinib- responsive genes. NPB001-05 showed additional genes selectively dysregulated from ER stress, PI3K/AKT, MAPK pathways. Additionally, we tested gene expression of PI3K, AKT1, JUN, CASP3 and DDIT3 in K562, BaF3P210(BCR-ABL) and BaF3 P210(BCR-ABLT315I) cell line treated for 6- and 12- hours with NPB001-05 and imatinib. The data indicates that NPB001-05 mediated cell death in K562 affects the function of ER stress. NPB001-05 shows antitumor activity with favorable toxicity profile.

NF-κB-mediated anti-inflammatory activity of the sesquiterpene lactone 7-hydroxyfrullanolide.

Microarray technology can be used to study the molecular mechanisms of new chemical entities with the aim to develop effective therapeutics. 7-Hydroxyfrullanolide (7HF) is a sesquiterpene lactone that was found to be efficacious in multiple animal models of inflammation by suppression of pro-inflammatory cytokines; however, its molecular mechanism of action remains unclear. We investigated the effects of 7HF on lipopolysaccharide (LPS)-stimulated human peripheral blood mononuclear cells using microarray-based gene expression studies and explored the molecular targets affected. Gene expression profiles and pathway analysis revealed that 7HF potently suppressed multiple inflammatory pathways induced by LPS. More importantly, 7HF was found to inhibit NF-κB related transcripts. These transcripts were further validated using freshly isolated synovial cells from rheumatoid arthritis patients, thus clinically validating our findings. Cell-based imaging and subsequent Western blot analysis demonstrated that 7HF inhibited the translocation of NF-κB into the nucleus by directly inhibiting the phosphorylation of IKK-ß. Since the transcription of adhesion molecules is regulated by NF-κB, further investigation showed that 7HF dose-dependently suppressed ICAM-1, VCAM-1 and E-selectin expression on LPS-stimulated endothelial cells as well as inhibited the adhesion of monocytes to LPS-stimulated endothelial cells. Taken together, our results reveal that 7HF possesses NF-κB inhibitory potential and suggest a likely molecular mechanism of its anti-inflammatory activity.

Phenotypic and genotypic assessment of concomitant drug-induced toxic effects in liver, kidney and blood.

Several studies have characterized drug-induced toxicity in liver and kidney. However, the majority of these studies have been performed with 'individual' organs in isolation. Separately, little is known about the role of whole blood as a surrogate tissue in drug-induced toxicity. Accordingly, we investigated the 'concurrent' response of liver, kidney and whole blood during a toxic assault. Rats were acutely treated with therapeutics (acetaminophen, rosiglitazone, fluconazole, isoniazid, cyclophosphamide, amphotericin B, gentamicin and cisplatin) reported for their liver and/or kidney toxicity. Changes in clinical chemistry parameters (e.g. AST, urea) and/or observed microscopic tissue damage confirmed induced hepatotoxicity and/or nephrotoxicity by all drugs. Drug-induced toxicity was not confined to an 'individual' organ. Not all drugs elicited significant alterations in phenotypic parameters of toxicity (e.g. ALT, creatinine). Accordingly, the transcriptional profile of the organs was studied using a toxicity panel of 30 genes derived from literature. Each of the test drugs generated specific gene expression patterns which were unique for all three organs. Hierarchical cluster analyses of purported hepatotoxicants and nephrotoxicants each led to characteristic 'fingerprints' (e.g. decrease in Cyp3a1 indicative of hepatotoxicity; increase in Spp1 and decrease in Gstp1 indicative of nephrotoxicity). In whole blood cells, a set of genes was derived which closely correlated with individual drug-induced concomitant changes in liver or kidney. Collectively, these data demonstrate drug-induced multi-organ toxicity. Furthermore, our findings underscore the importance of transcriptional profiling during inadequate phenotypic anchorage and suggest that whole blood may be judiciously used as a surrogate for drug-induced extra-hematological organ toxicity.

Effect of nephrotoxicants and hepatotoxicants on gene expression profile in human peripheral blood mononuclear cells.

Studying peripheral blood transcriptome in the quest for translational markers of toxicity is considered to be an attractive offshoot in the field of toxicogenomics. Moreover, it is acknowledged that, xenobiotics which cause a toxic response through similar mechanisms lead to distinctive gene expression patterns. The current study was undertaken to gauge the response of an accessible surrogate tissue, such as blood, to drug-induced perturbations aimed at deriving gene expression patterns. Human peripheral blood mononuclear cells (hPBMC) were exposed to conventional drugs, with reported kidney and/or liver injury, in order to determine their transcriptomic response. Test drugs were divided into two classes viz., drugs affecting kidney (cyclophosphamide, amphotericin B, gentamicin and cisplatin) and liver (acetaminophen, rosiglitazone, fluconazole and isoniazid). After performing gene expression analysis and hierarchical clustering, signature patterns for the two classes were obtained, with a set of 365 genes that can discriminate the two classes of drugs. Our results imply that transcriptional profile of hPBMC get altered as a consequence of drug exposure and unique patterns indicative of specific organ toxicity can hence be deduced. These signature patterns obtained for drugs could be studied for their qualification to identify drug-induced toxicity.