BCG skin reaction in Mantoux-negative healthy children

BACKGROUND: Tuberculosis poses a great challenge, especially in children. The response of BCG Test may be different in previously vaccinated children and needs to be considered before interpreting positivity for TB. This study has been carried out to determine the pattern of BCG reaction comparing previously vaccinated with non-vaccinated children. METHODS: The study was conducted in the healthy school children aged 4–6 years. The BCG skin reaction in Mantoux-negative children was compared between children with and without previous BCG scar. After the Mantoux and BCG Test, the analysis of variance was done as per protocol. RESULTS: Out of 50 children previously BCG vaccinated, 39(78%) showed exaggerated BCG test responses while out of another 50 children who were not vaccinated for TB, only 9(18%) showed exaggerated BCG Test response (p-value < 0.00001). Average induration obtained in children who were immunized with BCG at birth was much greater than those who were not immunized. 80% and 76% males and females respectively in Group I showed exaggerated BCG response while 16% and 20% males and females respectively of Group II showed exaggerated BCG response. CONCLUSION: The present study indicates that normal healthy children may have a mild exaggerated BCG Test response i.e. induration up to 8 mm because of prior BCG vaccination. Therefore, BCG Test, though important should not be the only criteria for start of chemotherapy for TB in children as the side effects of drugs may cause much morbidity. An induration up to 8 mm after the BCG Test can be normal in Indian settings due to exposure to Mycobacterium in environment and/or BCG vaccine

Democratizing LLMs: An Exploration of Cost-Performance Trade-offs in Self-Refined Open-Source Models

The dominance of proprietary LLMs has led to restricted access and raised information privacy concerns. High-performing open-source alternatives are crucial for information-sensitive and high-volume applications but often lag behind in performance. To address this gap, we propose (1) A untargeted variant of iterative self-critique and self-refinement devoid of external influence. (2) A novel ranking metric - Performance, Refinement, and Inference Cost Score (PeRFICS) - to find the optimal model for a given task considering refined performance and cost. Our experiments show that SoTA open source models of varying sizes from 7B - 65B, on average, improve 8.2% from their baseline performance. Strikingly, even models with extremely small memory footprints, such as Vicuna-7B, show a 11.74% improvement overall and up to a 25.39% improvement in high-creativity, open ended tasks on the Vicuna benchmark. Vicuna-13B takes it a step further and outperforms ChatGPT post-refinement. This work has profound implications for resource-constrained and information-sensitive environments seeking to leverage LLMs without incurring prohibitive costs, compromising on performance and privacy. The domain-agnostic self-refinement process coupled with our novel ranking metric facilitates informed decision-making in model selection, thereby reducing costs and democratizing access to high-performing language models, as evidenced by case studies.Comment: Accepted to Findings of EMNLP 202

A review of multi-criteria decision making techniques for supplier evaluation and selection

Supplier evaluation and selection has been a vital issue of strategic importance for long time. Different multi-criteria decision making (MCDM) approaches have been proposed by the researchers in past, to solve the supplier evaluation and selection problem. In this paper, we present a review of various MCDM methodologies reported in the literature for solving the supplier evaluation and selection process. The review is solely based on sixty-eight research articles, including eight review articles in the academic literature from 2000 to 2011. We try to find out the most prevalent approach in the articles and thereby present the future scope of arriving at an optimal solution to the problem, based on the specifications, the strategies and the requirements of the buyers. The study presents that with the change in processes and the requirements, how the approach of the manufacturing industry has shifted from striving for operational effectiveness to the strategic partnership in the dyadic relationship

Targeting BET bromodomain proteins in solid tumors

There is increasing interest in inhibitors targeting BET (bromodomain and extra-terminal) proteins because of the association between this family of proteins and cancer progression. BET inhibitors were initially shown to have efficacy in hematologic malignancies; however, a number of studies have now shown that BET inhibitors can also block progression of non-hematologic malignancies. In this Review, we summarize the efficacy of BET inhibitors in select solid tumors; evaluate the role of BET proteins in mediating resistance to current targeted therapies; and consider potential toxicities of BET inhibitors. We also evaluate recently characterized mechanisms of resistance to BET inhibitors; summarize ongoing clinical trials with these inhibitors; and discuss potential future roles of BET inhibitors in patients with solid tumors

Profiling Heterogeneous Circulating Tumor Cells (CTC) Populations in Pancreatic Cancer Using a Serial Microfluidic CTC Carpet Chip

Although isolation of circulating tumor cells (CTCs) from pancreatic adenocarcinoma patients is feasible, investigating their clinical utility has proven less successful than other cancers due to the limitations of epithelial cellular adhesion molecule (EpCAM)‐only based CTC assays. An integrated technology‐ and biology‐based approach using a microfluidic “Carpet Chip” is presented to study the biological relevance of heterogeneous CTC populations. Both epithelial CTCs (EpCs) and epithelial‐to‐mesenchymal transition (EMT)‐like CTCs (EMTCs) are isolated simultaneously from the whole blood of pancreatic cancer (PaCa) patients (n = 35) by separately targeting two surface markers: EpCAM and CD133. Recovery of cancer cell lines spiked into whole blood is ≥97% with >76% purity. Thirty‐four patients had ≥5 EpCs mL−1 and 35 patients had ≥15 EMTCs mL−1. Overall, significantly higher numbers of EMTCs than EpCs are recovered, reflecting the aggressive nature of PaCa. Furthermore, higher numbers of EMTCs are observed in patients with lymph node involvement compared to patients without. Gene expression profiling of CTCs from 17 patients reveals that CXCR1 is significantly upregulated in EpCs, while known stem cell markers POU5F1/Oct‐4 and MYC are upregulated in EMTCs. In conclusion, successful isolation and genomic profiling of heterogeneous CTC populations are demonstrated, revealing genetic signatures relevant to patient outcomes.“Carpet Chip” uses sequential immunoaffinity‐based microfluidics to study the biological relevance of heterogeneous circulating tumor cell (CTCs). Both epithelial (EpCs) and epithelial‐to‐mesenchymal transition (EMT)‐like CTCs (EMTCs) are detectable from the blood of pancreatic cancer patients. Based on our observations of EMTCs and patient lymph node involvement, individualizing therapies targeting genes involved in EMT could reduce metastasis, thereby improving patient survival.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/147173/1/adbi201800228-sup-0001-S1.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/147173/2/adbi201800228.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/147173/3/adbi201800228_am.pd

Pancreatic cancer is marked by complement-high blood monocytes and tumor-associated macrophages

Pancreatic ductal adenocarcinoma (PDA) is accompanied by reprogramming of the local microenvironment, but changes at distal sites are poorly understood. We implanted biomaterial scaffolds, which act as an artificial premetastatic niche, into immunocompetent tumor-bearing and control mice, and identified a unique tumor-specific gene expression signature that includes high expression of C1qa, C1qb, Trem2, and Chil3 Single-cell RNA sequencing mapped these genes to two distinct macrophage populations in the scaffolds, one marked by elevated C1qa, C1qb, and Trem2, the other with high Chil3, Ly6c2 and Plac8 In mice, expression of these genes in the corresponding populations was elevated in tumor-associated macrophages compared with macrophages in the normal pancreas. We then analyzed single-cell RNA sequencing from patient samples, and determined expression of C1QA, C1QB, and TREM2 is elevated in human macrophages in primary tumors and liver metastases. Single-cell sequencing analysis of patient blood revealed a substantial enrichment of the same gene signature in monocytes. Taken together, our study identifies two distinct tumor-associated macrophage and monocyte populations that reflects systemic immune changes in pancreatic ductal adenocarcinoma patients

Synergistic Analysis of Circulating Tumor Cells Reveals Prognostic Signatures in Pilot Study of Treatment-Naïve Metastatic Pancreatic Cancer Patients

Pancreatic ductal adenocarcinoma is typically diagnosed at late stages and has one of the lowest five-year survival rates of all malignancies. In this pilot study, we identify signatures related to survival and treatment response found in circulating tumor cells (CTCs). Patients with poor survival had increased mutant KRAS expression and deregulation of connected pathways such as PI3K-AKT and MAPK signaling. Further, in a subset of these patients, expression patterns of gemcitabine resistance mechanisms were observed, even prior to initiating treatment. This work highlights the need for identifying patients with these resistance profiles and designing treatment regimens to circumvent these mechanisms

Three-dimensional collagen I promotes gemcitabine resistance in vitro in pancreatic cancer cells through HMGA2-dependent histone acetyltransferase expression.

Pancreatic ductal adenocarcinoma (PDAC) is associated with a pronounced collagen-rich stromal reaction that has been shown to contribute to chemo-resistance. We have previously shown that PDAC cells are resistant to gemcitabine chemotherapy in the collagen microenvironment because of increased expression of the chromatin remodeling protein high mobility group A2 (HMGA2). We have now found that human PDAC tumors display higher levels of histone H3K9 and H3K27 acetylation in fibrotic regions. We show that relative to cells grown on tissue culture plastic, PDAC cells grown in three-dimensional collagen gels demonstrate increased histone H3K9 and H3K27 acetylation, along with increased expression of p300, PCAF and GCN5 histone acetyltransferases (HATs). Knocking down HMGA2 attenuates the effect of collagen on histone H3K9 and H3K27 acetylation and on collagen-induced p300, PCAF and GCN5 expression. We also show that human PDAC tumors with HMGA2 demonstrate increased histone H3K9 and H3K27 acetylation. Additionally, we show that cells in three-dimensional collagen gels demonstrate increased protection against gemcitabine. Significantly, down-regulation of HMGA2 or p300, PCAF and GCN5 HATs sensitizes the cells to gemcitabine in three-dimensional collagen. Overall, our results increase our understanding of how the collagen microenvironment contributes to chemo-resistance in vitro and identify HATs as potential therapeutic targets against this deadly cancer