Diabetes mellitus in acute exacerbation of chronic obstructive pulmonary disease - the tip of the iceberg.

COPD is a chronic respiratory disease characterized by systemic inflammation caused primarily by tobacco use, and it is associated with an increased susceptibility to respiratory infections, both viral and bacterial, which are responsible for acute COPD exacerbations (AECOPD). Diabetes mellitus is one of the most common co-morbidities in COPD patients. In our study, we attempted to detect previously undiagnosed diabetes in AECOPD patients who presented to our Institute. The study included 100 patients who had been diagnosed with AECOPD. Pearson's coefficient correlation analysis was used to assess the relationship between various parameters. The vast majority of patients belonged to Group 3. (diagnosed at the time of admission as having type II diabetes). HbA1c had a significant positive correlation with BMI, cholesterol, and TLC, but a negative correlation with SpO2. Using HbA1C, nearly two-thirds of the AECOPD were newly diagnosed with diabetes mellitus. Our findings suggest that diabetes is significantly underdiagnosed in COPD patients.

Point-of-care test for tuberculosis: a boon in diagnosis.

Rapid diagnosis of tuberculosis (TB) is an effective measure to eradicate this infectious disease worldwide. Traditional methods for screening TB patients do not provide an immediate diagnosis and thus delay treatment. There is an urgent need for the early detection of TB through point-of-care tests (POCTs). Several POCTs are widely available at primary healthcare facilities that assist in TB screening. In addition to the currently used POCTs, advancements in technology have led to the discovery of newer methods that provide accurate and fast information independent of access to laboratory facilities. In the present article, the authors tried to include and describe the potential POCTs for screening TB in patients. Several molecular diagnostic tests, such as nucleic acid amplification tests, including GeneXpert and TB-loop-mediated isothermal amplification, are currently being used as POCTs. Besides these methods, the pathogenic component of Mycobacterium tuberculosis can also be utilized as a biomarker for screening purposes through immunological assays. Similarly, the host immune response to infection has also been utilized as a marker for the diagnosis of TB. These novel biomarkers might include Mtb85, interferon-γ inducible protein-10, volatile organic compounds, acute-phase proteins, etc. Radiological tests have also been observed as POCTs in the TB screening POCT panel. Various POCTs are performed on samples other than sputum, which further eases the screening process. These POCTs should not require large-scale manpower and infrastructure. Hence, POCT should be able to identify patients with M. tuberculosis infection at the primary healthcare level only. There are several other advanced techniques that have been proposed as future POCTs and have been discussed in the present article.

Discoidin Domain Receptor-Driven Gene Signatures as Markers of Patient Response to Anti-PD-L1 Immune Checkpoint Therapy.

BACKGROUND: Anti-programmed cell death 1 (anti-PD-1) and PD ligand 1 (PD-L1) immune checkpoint therapies (ICTs) provided durable responses only in a subset of cancer patients. Thus, biomarkers are needed to predict nonresponders and offer them alternative treatments. We recently implicated discoidin domain receptor tyrosine kinase 2 (DDR2) as a contributor to anti-PD-1 resistance in animal models; therefore, we sought to investigate whether this gene family may provide ICT response prediction. METHODS: We assessed mRNA expression of DDR2 and its family member DDR1. Transcriptome analysis of bladder cancer (BCa) models in which DDR1 and 2 were perturbed was used to derive DDR1- and DDR2-driven signature scores. DDR mRNA expression and gene signature scores were evaluated using BCa-The Cancer Genome Atlas (n = 259) and IMvigor210 (n = 298) datasets, and their relationship to BCa subtypes, pathway enrichment, and immune deconvolution analyses was performed. The potential of DDR-driven signatures to predict ICT response was evaluated and independently validated through a statistical framework in bladder and lung cancer cohorts. All statistical tests were 2-sided. RESULTS: DDR1 and DDR2 showed mutually exclusive gene expression patterns in human tumors. DDR2high BCa exhibited activation of immune pathways and a high immune score, indicative of a T-cell-inflamed phenotype, whereas DDR1high BCa exhibited a non-T-cell-inflamed phenotype. In IMvigor210 cohort, tumors with high DDR1 (hazard ratio [HR] = 1.53, 95% confidence interval [CI] = 1.16 to 2.06; P = .003) or DDR2 (HR = 1.42, 95% CI = 1.01 to 1.92; P = .04) scores had poor overall survival. Of note, DDR2high tumors from IMvigor210 and CheckMate 275 (n = 73) cohorts exhibited poorer overall survival (HR = 1.56, 95% CI = 1.20 to 2.06; P < .001) and progression-free survival (HR = 1.77 95%, CI = 1.05 to 3.00; P = .047), respectively. This result was validated in independent cancer datasets. CONCLUSIONS: These findings implicate DDR1 and DDR2 driven signature scores in predicting ICT response.

Integration of tumor extrinsic and intrinsic features associates with immunotherapy response in non-small cell lung cancer.

The efficacy of immune checkpoint blockade (ICB) varies greatly among metastatic non-small cell lung cancer (NSCLC) patients. Loss of heterozygosity at the HLA-I locus (HLA-LOH) has been identified as an important immune escape mechanism. However, despite HLA-I disruptions in their tumor, many patients have durable ICB responses. Here we seek to identify HLA-I-independent features associated with ICB response in NSCLC. We use single-cell profiling to identify tumor-infiltrating, clonally expanded CD4+ T cells that express a canonical cytotoxic gene program and NSCLC cells with elevated HLA-II expression. We postulate cytotoxic CD4+ T cells mediate anti-tumor activity via HLA-II on tumor cells and augment HLA-I-dependent cytotoxic CD8+ T cell interactions to drive ICB response in NSCLC. We show that integrating tumor extrinsic cytotoxic gene expression with tumor mutational burden is associated with longer time to progression in a real-world cohort of 123 NSCLC patients treated with ICB regimens, including those with HLA-LOH.

Clinical, Genomic, and Transcriptomic Data Profiling of Biliary Tract Cancer Reveals Subtype-Specific Immune Signatures.

PURPOSE: Biliary tract cancers (BTCs) are aggressive cancers that carry a poor prognosis. An enhanced understanding of the immune landscape of anatomically and molecularly defined subsets of BTC may improve patient selection for immunotherapy and inform immune-based combination treatment strategies. METHODS: We analyzed deidentified clinical, genomic, and transcriptomic data from the Tempus database to determine the mutational frequency and mutational clustering across the three major BTC subtypes (intrahepatic cholangiocarcinoma [IHC], extrahepatic cholangiocarcinoma, and gallbladder cancer). We subsequently determined the relationship between specific molecular alterations and anatomical subsets and features of the BTC immune microenvironment. RESULTS: We analyzed 454 samples of BTC, of which the most commonly detected alterations were TP53 (42.5%), CDKN2A (23.4%), ARID1A (19.6%), BAP1 (15.5%), KRAS (15%), CDKN2B (14.2%), PBRM1 (11.7%), IDH1 (11.7%), TERT (8.4%), KMT2C (10.4%) and LRP1B (8.4%), and FGFR2 fusions (8.7%). Potentially actionable molecular alterations were identified in 30.5% of BTCs including 39.1% of IHC. Integrative cluster analysis revealed four distinct molecular clusters, with cluster 4 predominately associated with FGFR2 rearrangements and BAP1 mutations in IHC. Immune-related biomarkers indicative of an inflamed tumor-immune microenvironment were elevated in gallbladder cancers and in cluster 1, which was enriched for TP53, KRAS, and ATM mutations. Multiple common driver genes, including TP53, FGFR2, IDH1, TERT, BRAF, and BAP1, were individually associated with unique BTC immune microenvironments. CONCLUSION: BTC subtypes exhibit diverse DNA alterations, RNA inflammatory signatures, and immune biomarkers. The association between specific BTC anatomical subsets, molecular alterations, and immunophenotypes highlights new opportunities for therapeutic development.

Significance of Morphometric and Anatomic Variations of Nasopalatine Canal on Cone-Beam Computed Tomography in Anterior Functional Zone - A Retrospective Study.

INTRODUCTION: Oral rehabilitation in maxillary anterior region has increased concerns in the dental fraternity to have detailed morphological examination in treatment planning. The nasopalatine canal (NPC) along with its contents plays an important role in determining the prognosis of implants and their associated surgeries. The present study was performed to evaluate morphometric anatomic variations of the NPC using focused small field of view on cone-beam computed tomography (CBCT). MATERIALS AND METHODS: The study included 250 participants. CBCT examination was conducted using standard exposure and patient positioning protocols. Sagittal, coronal, and axial sections were reviewed to determine NPC morphology and dimensions. RESULTS: Single, round, incisive foramen with mean mesiodistal diameter of 3.23 (±1.00) mm, and mean anteroposterior dimension of 3.03 (±0.96) mm was found. Single Stenson's foramen along with funnel shaped, slanted NPC with mean angulation of 81.97 (±42.19), and mean length of 12.67 (±2.69) mm was found. Mean mesiodistal diameter at nasal fossa of NPC was 3.27 (±1.75) mm, at mid-level was 2.23 (±1.02) mm, at palate was 3.46 (±1.12) mm. At least one additional foramen was found. DISCUSSION: Anatomy of the NPC is highly variable. Age-wise and gender-wise correlations revealed statistically significant results for different parameters. The present study highlighted significance of NPC along with its variations. Therefore, a methodical three-dimensional presurgical assessment is mandatory before any surgical intervention in this region.

Prognostic and therapeutic relevance of cathepsin B in pediatric acute myeloid leukemia.

AML, the second most common childhood leukemia is also one of the deadliest cancers. High mortality rate in AML is due to high incidence of relapse after complete remission with chemotherapy and inadequate prognostic assessment of patients. Moreover, there is dearth of therapeutic targets for treatment of this malignancy. Previous pilot study (n = 24) by our group revealed strong association between cathepsin B (CTSB) overexpression in peripheral blood mononuclear cells (PBMCs) and poor survival outcome in pediatric AML patients. To further explore the clinical utility and role of this protease in pediatric AML, we measured its enzymatic activity and mRNA expression in PBMCs as well as bone marrow mononuclear cells (BMMCs) of patients (n = 101) and PBMCs of healthy controls. Our results revealed elevated CTSB activity (P < 0.01) and overexpression of its mRNA (P < 0.01) in AML patients. Interestingly CTSB in BMMCs of patients emerged as an independent prognostic marker when compared with other known risk factors. Moreover, chemical inhibition of CTSB activity compromised survival, and induced apoptosis in an AML cell line THP-1. We further demonstrate the inhibition of CTSB activity by chemotherapeutic agent doxorubicin in these cells. Docking and simulation studies suggested the binding of doxorubicin to CTSB with higher affinity than its known specific inhibitor CA-074 Me, thereby indicating that cell death induced by this drug may at least partly be mediated by CTSB inhibition. CTSB, therefore, may serve as a prognostic marker and an attractive chemotherapeutic target in pediatric AML.

Hybrid Ameloblastoma of Anterior Maxilla: A Rare and Puzzling Pathologic entity - Case Report with Systematic Review.

Hybrid ameloblastoma has a variable clinical, radiological, and histopathological presentation. They contain two or more different histologic types and their biologic comportment is still arguable. We herein present a case of a hybrid variant of desmoplastic ameloblastoma which is the first of its kind to have ever been reported due to its unusual location in the maxillary anterior region, along with systematic review of clinicopathologic features of reported cases immunohistochemical markers may act as an adjunct in the accurate diagnosis of these lesions.

Prognostic significance of cathepsin L expression in pediatric acute myeloid leukemia.

Overexpression of cathepsin L (CTSL), an endolysosomal cysteine protease, is associated with inferior survival of patients with various human malignancies. We evaluated the expression/activity of CTSL in peripheral blood mononuclear cells (PBMCs) and bone marrow mononuclear cells (BMMCs) of 103 pediatric acute myeloid leukemia (AML) patients to assess its prognostic significance in this malignancy. Thirty-five healthy siblings of patients served as controls. Our results revealed significantly higher CTSL activity (p < .0001), protein (p < .05), and mRNA levels (p < .01) in both PBMCs and BMMCs of patients as compared with controls. BMMCs displayed higher activity of CTSL than PBMCs (p < .01). A dramatic reduction in CTSL activity was recorded after chemotherapy in a significant proportion (74%) of patients (p < .0001). By multivariate analysis, CTSL in BMMCs emerged as a strong independent prognostic marker for overall survival (OS) (p = .004). Thus, our results suggest the potential utility of CTSL in predicting the outcome of pediatric AML.