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Enteric fever is a highly fatal infectious disease that can present with extensive symptoms that renders diagnosis quite risky. Multi-drug resistant Salmonella typhi infection has become endemic in third world countries and has been routinely associated with catastrophic complications and even death, with diagnostic and therapeutic impedance. Typhoid fever is known to cause life-threatening cerebral complications. We report the case of a 16-year-old male who presented to us with a high-grade fever, watery diarrhoea, altered level of consciousness, and a mixed dark-coloured crusted oral lesion. Blood workup showed neutropenia, lymphocytopenia, thrombocytopenia, transaminitis, and hyponatraemia. Blood culture grew multi-drug resistant Salmonella Typhi. CT scan of the brain showed diffuse cerebral oedema, while EEG was consistent with the diagnosis of diffuse encephalitis. The patient responded well to culture-sensitive antibiotics, while the oral lesion showed a dramatic response to presumptive antifungal treatment. ---Continue

KIN17 DNA and RNA binding protein (Kin17) is involved in the regulation of tumorigenesis of diverse human cancers. However, its role in the cancer progression and metastasis in hepatocellular carcinoma (HCC) remains largely unknown. Bioinformatics and immunohistochemistry staining were used to investigate the expression pattern of KIN17 and its prognostic value in HCC patients. The transwell, wound-healing assay was employed to determine the effects of KIN17 on migration and invasion of HCC cells in vitro. The tail veins model was employed to determine the effects of KIN17 on lung metastasis in vivo. The biological mechanisms involved in cell migration and invasion regulated by KIN17 were determined with Western blot analysis method. KIN17 expression was significantly increased in HCC tissues compared with adjacent normal tissues, with particularly higher in portal vein tumor thrombus and intrahepatic metastasis tissues. Patients with higher KIN17 expression experienced poor overall and disease free survival. KIN17 knockdown in HuH7 and HepG2 cells significantly reduced cell migration and invasion abilities, whereas its overexpression promoted migration and invasion in MHCC-97L and HepG2 cells in vitro and in vivo. In HuH7 and HepG2 cells, KIN17 knockdown inhibited the TGF-β/Smad2 pathway. In contrast, KIN17 overexpression stimulated TGF-β/Smad2 pathway in MHCC-97L and HepG2 cells, along with the genes involved in the epithelial-mesenchymal transition. These findings suggest that KIN17 promotes migration and invasion in HCC cells by stimulating the TGF-β/Smad2 pathway. KIN17 could be a promising prognostic biomarker, as well as a potential therapeutic target in HCC.

Objective: To investigate the efficacy of ivermectin in the treatment of mild, moderate, and severe COVID-19 infection. Study Design: Retrospective Cohort study. Setting: COVID-19 Treatment Centre, Dr. Ruth K M Pfau Civil Hospital Karachi. Period: July 2020 to December 2020. Material & Methods: Medical records of 423 patients during a selected duration of 6 months were reviewed. Patients were stratified into two groups based on whether or not they received a 6-day course of ivermectin in addition to the standard treatment for COVID-19. Primary outcome measures were rate of mortality, days from the start of treatment to negative SARS-CoV-2 PCR, and rate of step-up to the intensive care unit. Results: Patients who received ivermectin required a lesser number of days (8.39 days ± 2.04) to become COVID negative than the patients who didn't receive ivermectin (20.38 days ± 6.32), (p < 0.001). Multinomial logistic regression showed that the patients who were given ivermectin for COVID 19 infection were four times more likely to be discharged home than stepping up to ICU. The ICU step-up rate in the ivermectin group was found to be 3.7% compared to 13.04% in the non-ivermectin group. No significant differences in mortality were found. Conclusion: Treatment with ivermectin in COVID-19 infection is associated with improved outcomes in terms of reduction in duration of illness as well as the progression of disease severity.

PURPOSE: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer that is frequently treated with chemotherapy. However, many patients exhibit either de novo chemoresistance or ultimately develop resistance to chemotherapy, leading to significantly high mortality rates. Therefore, increasing the efficacy of chemotherapy has potential to improve patient outcomes. METHODS: Here, we performed whole transcriptome sequencing (both RNA and small RNA-sequencing), coupled with network simulations and patient survival data analyses to build a novel miRNA-mRNA interaction network governing chemoresistance in TNBC. We performed cell proliferation assay, Western blotting, RNAi/miRNA mimic experiments, FN coating, 3D cultures, and ChIP assays to validate the interactions in the network, and their functional roles in chemoresistance. We developed xenograft models to test the therapeutic potential of the identified key miRNA/proteins in potentiating chemoresponse in vivo. We also analyzed several patient datasets to evaluate the clinical relevance of our findings. RESULTS: We identified fibronectin (FN1) as a central chemoresistance driver gene. Overexpressing miR-326 reversed FN1-driven chemoresistance by targeting FN1 receptor, ITGA5. miR-326 was downregulated by increased hypoxia/HIF1A and ECM stiffness in chemoresistant tumors, leading to upregulation of ITGA5 and activation of the downstream FAK/Src signaling pathways. Overexpression of miR-326 or inhibition of ITGA5 overcame FN1-driven chemotherapy resistance in vitro by inhibiting FAK/Src pathway and potentiated the efficacy of chemotherapy in vivo. Importantly, lower expression of miR-326 or higher levels of predicted miR-326 target genes was significantly associated with worse overall survival in chemotherapy-treated TNBC patients. CONCLUSION: FN1 is central in chemoresistance. In chemoresistant tumors, hypoxia and resulting ECM stiffness repress the expression of the tumor suppressor miRNA, miR-326. Hence, re-expression of miR-326 or inhibition of its target ITGA5 reverses FN1-driven chemoresistance making them attractive therapeutic approaches to enhance chemotherapy response in TNBCs.

Purpose: Tamoxifen remains an important hormonal therapy for ER-positive breast cancer; however, development of resistance is a major obstacle in clinics. Here, we aimed to identify novel mechanisms of tamoxifen resistance and provide actionable drug targets overcoming resistance.Experimental Design: Whole-transcriptome sequencing, downstream pathway analysis, and drug repositioning approaches were used to identify novel modulators [here: phosphodiesterase 4D (PDE4D)] of tamoxifen resistance. Clinical data involving tamoxifen-treated patients with ER-positive breast cancer were used to assess the impact of PDE4D in tamoxifen resistance. Tamoxifen sensitization role of PDE4D was tested in vitro and in vivo. Cytobiology, biochemistry, and functional genomics tools were used to elucidate the mechanisms of PDE4D-mediated tamoxifen resistance.Results: PDE4D, which hydrolyzes cyclic AMP (cAMP), was significantly overexpressed in both MCF-7 and T47D tamoxifen-resistant (TamR) cells. Higher PDE4D expression predicted worse survival in tamoxifen-treated patients with breast cancer (n = 469, P = 0.0036 for DMFS; n = 561, P = 0.0229 for RFS) and remained an independent prognostic factor for RFS in multivariate analysis (n = 132, P = 0.049). Inhibition of PDE4D by either siRNAs or pharmacologic inhibitors (dipyridamole and Gebr-7b) restored tamoxifen sensitivity. Sensitization to tamoxifen is achieved via cAMP-mediated induction of unfolded protein response/ER stress pathway leading to activation of p38/JNK signaling and apoptosis. Remarkably, acetylsalicylic acid (aspirin) was predicted to be a tamoxifen sensitizer using a drug repositioning approach and was shown to reverse resistance by targeting PDE4D/cAMP/ER stress axis. Finally, combining PDE4D inhibitors and tamoxifen suppressed tumor growth better than individual groups in vivo.Conclusions: PDE4D plays a pivotal role in acquired tamoxifen resistance via blocking cAMP/ER stress/p38-JNK signaling and apoptosis. Clin Cancer Res; 24(8); 1987–2001. ©2018 AACR.

Mishra and Sahin patent info for Conflict of Interest

SUPPLEMENTARY FIGURE 1 Correlation of VIM/CDH1 ratios in different datasets. The list of 35 genes significantly correlated with EMT. Lack of correlation between AKR1B10 mRNA levels and EMT. SUPPLEMENTARY FIGURE 2 AKR1B1 levels are modulated by ZEB1, but not in a direct fashion. SUPPLEMENTARY FIGURE 3 Characteristics of the NSCLC patients stained with immunohistochemistry and impact on survival. Alterations of AKR1B1 levels influence cancer cells growth and cancer stemness. SUPPLEMENTARY FIGURE 4 Impact of SORD knockdown on cancer cells growth and invasion. The combination of the inhibition of polyol pathway gene and cisplatin suppresses in vitro growth. Oxidative consumption rate and ECAR/OCR ratios in polyol pathway-deficient cells. SUPPLEMENTARY FIGURE 5 Co-expression patterns of AKR1B1 and SORD in TCGA datasets. SUPPLEMENTARY FIGURE 6 Effects of treatment with excess glucose on the generation of polyols, on the alteration of EMT and stemness markers, and on the activation of TGF-Beta signaling and TGF-Beta-related genes.

This file contains supplementary methods, 7 supplementary figures and 5 supplementary tables.

List of differentially expressed genes in all analyzed datasets

Cancer cells alter their metabolism to support their malignant properties. In this study, we report that the glucose-transforming polyol pathway (PP) gene aldo-keto-reductase-1-member-B1 (AKR1B1) strongly correlates with epithelial-to-mesenchymal transition (EMT). This association was confirmed in samples from lung cancer patients and from an EMT-driven colon cancer mouse model with p53 deletion. In vitro, mesenchymal-like cancer cells showed increased AKR1B1 levels, and AKR1B1 knockdown was sufficient to revert EMT. An equivalent level of EMT suppression was measured by targeting the downstream enzyme sorbitol-dehydrogenase (SORD), further pointing at the involvement of the PP. Comparative RNA sequencing confirmed a profound alteration of EMT in PP-deficient cells, revealing a strong repression of TGFβ signature genes. Excess glucose was found to promote EMT through autocrine TGFβ stimulation, while PP-deficient cells were refractory to glucose-induced EMT. These data show that PP represents a molecular link between glucose metabolism, cancer differentiation, and aggressiveness, and may serve as a novel therapeutic target.Significance: A glucose-transforming pathway in TGFβ-driven epithelial-to-mesenchymal transition provides novel mechanistic insights into the metabolic control of cancer differentiation. Cancer Res; 78(7); 1604–18. ©2018 AACR.

The COVID-19 pandemic of 2019 meant higher education was forced to delivering education online. For most, the transition to emergency remote teaching was a natural next step to support continuity of education. However, there were some examples where education remained on campus. Where after taking all COVID-19 safety measures of social distancing, hand hygiene measures and other health protocols, institutions decided to continue to deliver face-to-face on-campus offerings with limited capacity. The COVID-19 and higher education literature have focused primarily on rapid digitalisation. This manuscript adds value to the literature by focusing on three case studies of on-campus delivery for faceto-face teaching in the classroom and practical lessons during the pandemic in Australia, the United Kingdom, and Pakistan. The changes to the learning process affected students’ interactions with the lecturer, other students, and the equipment they were learning to use. Also, it affected interactions with each other in practical activities due to limited numbers of participants, motivation in learning and achieving learning outcomes. Not only the students, but the lecturer’s capability in delivering the course was affected by fatigue due to spending more time teaching within a ‘COVID-19 safe’ environment. This study will provide important documentation on the effect of COVID-19 on on-campus delivery, as well as opportunities to support greater student engagement in class environments through the sharing of learning equipment, fostering positive motivation, managing learning outcomes, and self-monitoring of lecturer capability in more highly stressful teaching and learning environments practical training affected.

In this paper, we will define a new metric space called n-gonal graphical b-metric space. We will also prove some fixed point theorems in said metric space and give suitable examples to illustrate our results. These results will help to solve many nonlinear convex models in machine learning and optimization by formulating them in fixed point schemes of optimization. Our paper opens the door for researchers to work in the intersecting area of machine learning and functional analysis in the frame work of [Formula: see text]-gonal graphical [Formula: see text]-metric space.

Managing the integrity of products and processes in a multi-stakeholder supply chain environment is a significant challenge. Many current solutions suffer from data fragmentation, lack of reliable provenance, and diverse protocol regulations across multiple distributions and processes. Amongst other solutions, Blockchain has emerged as a leading technology, since it provides secure traceability and control, immutability, and trust creation among stakeholders in a low cost IT solution. Although Blockchain is making a significant impact in many areas, there are many impediments to its widespread adoption in supply chains. This article is the first survey of its kind, with detailed analysis of the challenges and future directions in Blockchain-enabled supply chains. We review the existing digitalization of the supply chain including the role of GS1 standards and technologies. Current use cases and startups in the field of Blockchain-enabled supply chains are reviewed and presented in tabulated form. Technical and non-technical challenges in the adoption of Blockchain for supply chain applications are critically analyzed, along with the suitability of various consensus algorithms for applications in the supply chain. The tools and technologies in the Blockchain ecosystem are depicted and analyzed. Some key areas as future research directions are also identified which must be addressed to realize mass adoption of Blockchain-based in supply chain traceability. Finally, we propose MOHBSChain, a novel framework for Blockchain-enabled supply chains.

The objective of this article is to establish some Hermite–Hadamard-type inequalities via harmonic s,m-convex functions in the framework of conformal fractional integral.

Chemoresistance is a major obstacle in triple negative breast cancer (TNBC), the most aggressive breast cancer subtype. Here we identify hypoxia-induced ECM re-modeler, lysyl oxidase (LOX) as a key inducer of chemoresistance by developing chemoresistant TNBC tumors in vivo and characterizing their transcriptomes by RNA-sequencing. Inhibiting LOX reduces collagen cross-linking and fibronectin assembly, increases drug penetration, and downregulates ITGA5/FN1 expression, resulting in inhibition of FAK/Src signaling, induction of apoptosis and re-sensitization to chemotherapy. Similarly, inhibiting FAK/Src results in chemosensitization. These effects are observed in 3D-cultured cell lines, tumor organoids, chemoresistant xenografts, syngeneic tumors and PDX models. Re-expressing the hypoxia-repressed miR-142-3p, which targets HIF1A, LOX and ITGA5, causes further suppression of the HIF-1α/LOX/ITGA5/FN1 axis. Notably, higher LOX, ITGA5, or FN1, or lower miR-142-3p levels are associated with shorter survival in chemotherapy-treated TNBC patients. These results provide strong pre-clinical rationale for developing and testing LOX inhibitors to overcome chemoresistance in TNBC patients., The development of chemoresistance is a major hurdle in triple negative breast cancer (TNBC). Here, the authors show that lysyl oxidase (LOX) is overexpressed in chemoresistant TNBCs, and when inhibited reduces collagen cross-linking, fibronectin fibril assembly, and downstream integrin signalling, overcoming resistance.

Content naming and lookup are decisive functions of the future architecture named data network (NDN). The core concept of NDN is the content distribution between consumers and content providers. The NDN supports advance vehicular networks that is famous with vehicular-named data network (VNDN) with different naming schemes such as hybrid, flat, attribute-based, and hierarchical names. These schemes are used in a static way for vehicular network, in summary, the hybrid, flat, and attribute-based makes a complex structure, and on the other hand, hierarchical names long in length and name lookup performance are a bottleneck in NDN, which can directly affect the network performance. Therefore, we introduce a dynamic naming scheme and lookup method (DNSL) for VNDN to mitigate these issues. We argue that the dynamic naming scheme is a better approach to VNDN, while the static name is a cost-effective, hefty, integrated fashion, and improper for the vehicular network. This study focuses on (1) a dynamic naming scheme using dynamic-tag and (2) a lookup method based on node partition of trie; the trie approach is very famed in data structure and extensively used for the lookup content, insertion, and deletion processes. Our experimental evaluation shows that the DNSL scheme is highly efficient, scalable, and provably correct for VNDN.

23 Background: Identification of factors associated with enrollment disparities in clinical trials can narrow cancer care inequities. Funding source can influence minority representation in clinical trials. Therefore, we aimed to assess the impact of funding sources on enrollment disparities in colorectal (CRC) clinical trials. Methods: CRC phase II/III randomized controlled trial (RCTs) identified through MEDLINE and EMBASE from each database’s inception through 2022 were considered eligible. Trial level enrollment incidence ratios (EIR) were computed; defined as the ratio of trial proportions of a gender, age, or racial/ethnic subgroup category and the global incidence in the corresponding gender/age subgroup (from the global burden of disease database), or the US-population-based incidence in the corresponding racial/ethnic subgroup (from SEER 21 database). EIRs were then meta-analyzed using a random-effects model for each funding source category (US- government, industry, others). Temporal trends were analyzed using a univariate meta-regression. Results: Using data from 287 RCTs, women were significantly under-represented in the industry sponsored trials (EIR: 0.85 [95% CI: 0.83 - 0.88]) but not in US-government sponsored trials (0.92 [0.84-1.00]). A total of 87 RCTs reported age proportions; older adults (above 65 years) were significantly under-represented in the industry sponsored (0.84 [0.74-0.96]) and as well as in US-government sponsored CRC trials (0.52 [0.44-0.61]). Only 56 and 15 trials reported race and ethnicity, respectively. Limited data on racial/ethnic enrollment revealed significant under-representation of Black (0.45 [0.36 -0.57]) and Hispanic (0.45 [0.31-0.66]) patients across industry sponsored CRC trials. In contrast, no significant disparity was observed in the inclusion of Asian race in the industry sponsored trials. The number of US-government sponsored trials reporting racial/ethnic subgroups were small ( < 10) which precluded any meaningful statistics. Trends show that the representation of women has improved ( P: 0.02) while the representation of Black ( P: 0.007) and Hispanic patients ( P: 0.04) has worsened over the last three decades in industry sponsored CRC trials. Conclusions: The reporting of race/ethnicity is suboptimal in CRC trials especially in those sponsored by US government. Older adults may be under-represented regardless of funding source. Women, Blacks and Hispanics may be under-represented in industry sponsored CRC clinical trials. While representation of women appears to be improving, representation of Black and Hispanic patients has worsened in industry sponsored CRC clinical trials over the last three decades.