Hypoxia Inducible Factor (HIF), the main actor in the cell response to hypoxia, represents a potential target in cancer therapy. HIF is involved in many biological processes such as cell proliferation, survival, apoptosis, angiogenesis, iron metabolism and glucose metabolism. This protein regulates the expressions of Lactate Dehydrogenase (LDH) and Pyruvate Dehydrogenase (PDH), both essential for the conversion of pyruvate to be used in aerobic and anaerobic pathways. HIF upregulates LDH, increasing the conversion of pyruvate into lactate which leads to higher secretion of lactic acid by the cell and reduced pH in the microenvironment. HIF indirectly downregulates PDH, decreasing the conversion of pyruvate into Acetyl Coenzyme A which leads to reduced usage of the Tricarboxylic Acid (TCA) cycle in aerobic pathways. Upregulation of HIF may promote the use of anaerobic pathways for energy production even in normal extracellular oxygen conditions. Higher use of glycolysis even in normal oxygen conditions is called the Warburg effect. In this paper, we focus on HIF variations during tumour growth and study, through a mathematical model, its impact on the two metabolic key genes PDH and LDH, to investigate its role in the emergence of the Warburg effect. Mathematical equations describing the enzymes regulation pathways were solved for each cell of the tumour represented in an agent-based model to best capture the spatio-temporal oxygen variations during tumour development caused by cell consumption and reduced diffusion inside the tumour. Simulation results show that reduced HIF degradation in normoxia can induce higher lactic acid production. The emergence of the Warburg effect appears after the first period of hypoxia before oxygen conditions return to a normal level. The results also show that targeting the upregulation of LDH and the downregulation of PDH could be relevant in therapy.
Ovarian cancer is commonly diagnosed in its late stages, and new treatment modalities are needed to improve patient outcomes and survival. We have recently established the synergistic effects of combination tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) and procaspase activating compound (PAC-1) therapies in granulosa cell tumours (GCT) of the ovary, a rare form of ovarian cancer, using a mathematical model of the effects of both drugs in a GCT cell line. Here, to understand the mechanisms of combined TRAIL and PAC-1 therapy, study the viability of this treatment strategy, and accelerate preclinical translation, we leveraged our mathematical model in combination with population pharmacokinetics (PopPK) models of both TRAIL and PAC-1 to expand a realistic heterogeneous cohort of virtual patients and optimize treatment schedules. Using this approach, we investigated treatment responses in this virtual cohort and determined optimal therapeutic schedules based on patient-specific pharmacokinetic characteristics. Our results showed that schedules with high initial doses of PAC-1 were required for therapeutic efficacy. Further analysis of individualized regimens revealed two distinct groups of virtual patients within our cohort: one with high PAC-1 elimination, and one with normal PAC-1 elimination. In the high elimination group, high weekly doses of both PAC-1 and TRAIL were necessary for therapeutic efficacy, however virtual patients in this group were predicted to have a worse prognosis when compared to those in the normal elimination group. Thus, PAC-1 pharmacokinetic characteristics, particularly clearance, can be used to identify patients most likely to respond to combined PAC-1 and TRAIL therapy. This work underlines the importance of quantitative approaches in preclinical oncology.
Intro: Long-term treatment with interferon-alfa (IFN) can reduce the disease burden of patients diagnosed with myeloproliferative neoplasms (MPN). Determining individual patient-responses to IFN-therapy may allow for efficient personalized treatment, reducing both drop out and disease burden. Methods: A mathematical model describing hematopoietic stem cells and the immune system is suggested. Considering the bone marrow and the blood allows for modelling disease dynamics both in the absence and presence of treatment. Through comprehensive modelling of the effects of IFN, the model was related to individualized patient-data consisting of longitudinal hematologic and molecular measurements. Treatment responses are modelled on a population-level, allowing for personalized predictions from a single pre-treatment data point. Results: Personalized fits were found to agree well with data. This allowed for a quantitative description of the treatment-response, yielding a mechanistic interpretation of differences between individual patients. Population-level treatment-responses were simulated. Based on pre-treatment data and the actual treatment scheduling, the population-level response was found to predict the treatment-response of particular patients accurately over a five-year period. Conclusion: Mechanism-based modelling of treatment effects demonstrates that hematologic and molecular observables can be predicted on the level of individual patients. Personalized patient-fits suggest that the effect of IFN-treatment can be quantified and interpreted through mathematical modelling, despite variation in hematologic and molecular response for different patients. Modelling suggests that both hematologic and molecular markers must be considered to avoid immediate relapse. Furthermore, personalized model-fits provides quantitative measures of the hematologic and molecular response, determining when treatment-cessation is appropriate. Proof-of-concept population-level modelling of treatment-responses from pre-treatment data successfully predicted clinical measures for a five-year period. This approach could have direct clinical relevance, offering expert guidance for clinical decisions about IFN-treatment of MPN-patients.
Bladder cancer is a common malignancy with over 80,000 estimated new cases and nearly 18,000 deaths per year in the United States alone. Therapeutic options for metastatic bladder cancer had not evolved much for nearly four decades, until recently, when five immune checkpoint inhibitors were approved by the FDA. Despite the activity of these drugs in some patients, the objective response rate for each is less than 25%. At the same time, fibroblast growth factor receptors (FGFRs) have been attractive drug targets for a variety of cancers, and in 2019 the FDA approved the first therapy targeted against FGFR3 for bladder cancer. Given the excitement around these new receptor tyrosine kinase and immune checkpoint targeted strategies, and the challenges they each may face on their own, emerging data suggest that combining these treatment options could lead to improved therapeutic outcomes. In this paper, we develop a mathematical model for FGFR3-mediated tumor growth and use it to investigate the impact of the combined administration of a small molecule inhibitor of FGFR3 and a monoclonal antibody against the PD-1/PD-L1 immune checkpoint. The model is carefully calibrated and validated with experimental data before survival benefits and dosing schedules are explored. Predictions of the model suggest that FGFR3 mutation reduces the effectiveness of anti-PD-L1 therapy, that there are regions of parameter space where each monotherapy can outperform the other, and that pretreatment with anti-PD-L1 therapy always results in greater tumor reduction even when anti-FGFR3 therapy is the more effective monotherapy.
MicroRNAs (miRNAs) are short (~22 nucleotides) non-coding RNAs that are often intricately integrated into the regulatory networks of various cellular processes and govern the cell fate decision making events associated with oncogenesis by regulating the gene expression through post-transcriptional modifications. miRNAs repress the target genes by either degrading the target mRNA or by inhibiting the process of translation. However, mathematical and computational modeling of miRNA-mediated target gene regulation in various cellular network motifs suggests that miRNAs play a much more complex role in cellular decision-making events. In this review, we give an overview of the quantitative insights obtained from such kind of mathematical modeling of miRNA mediated gene regulation by highlighting the various factors associated with miRNA regulation that are pivotal in diversifying the cell fate decisions related to oncogenesis. Intriguingly, recent experiments suggest that miRNAs can even upregulate the translation of the target protein under certain circumstances, which may lead to more complexities in miRNA-mediated gene regulations. We discussed possible avenues to explore such unusual biological observations related to miRNA’s that can be modeled to get a detailed understanding of the influence of miRNAs in the context of oncogenesis.
Once cancer is initiated, with normal cells mutated into malignant ones, a solid tumour grows, develops and spreads within its microenvironment invading the local tissue; the disease progresses and the cancer cells migrate around the body leading to metastasis, the formation of distant secondary tumours. Interactions between the tumour and its microenvironment drive this cascade of events which have devastating, if not fatal, consequences for the human host/patient. Among these interactions, biomechanical interactions are a vital component. In this paper, key biomechanical relationships are discussed through a review of modelling efforts by the mathematical and computational oncology community. The main focus is directed, naturally, towards lattice-free agent-based, force-based models of solid tumour growth and development. In such models interactions between pairs of cancer cells (as well as between cells and other structures of the tumour microenvironment) are governed by forces. These forces are ones of repulsion and adhesion, and are typically modelled via either an extended Hertz model of contact mechanics or using Johnson-Kendal-Roberts theory, both of which are discussed here. The role of the extracellular matrix in determining disease progression is outlined along with important cell-vessel interactions which combined together account for a great proportion of Hanahan and Weinberg’s “Hallmarks of Cancer”.
Introduction: The use of prostate-specific antigen (PSA) as a prognostic indicator for prostate cancer (PCa) patients is controversial, especially since it has been shown to correlate poorly with tumor burden. The poor quality of PSA as a biomarker could be explained by current guidelines not accounting for the mechanism by which it enters circulation. Given that mature blood vessels are relatively impermeable to it, we hypothesize that immature and leaky blood vessels, formed under angiogenic cues in a hypoxic tumor, facilitate PSA extravasation into circulation. Methods: To explore our hypotheses, we develop a nonlinear dynamical systems model describing the vascular growth of PCa, that explicitly links PSA leakage into circulation with changes in intra-tumoral oxygen tension and vessel permeability. The model is calibrated versus serum PSA and tumor burden time-courses from a mouse xenograft model of castration resistant PCa response to androgen deprivation. Results: The model recapitulates the experimentally observed – and counter-intuitive – phenomenon of increasing tumor burden despite decreasing serum PSA levels. The validated model is then extended to the human scale by incorporating patient-specific parameters and fitting individual PSA time-courses from patients with biochemically failing PCa. Our results highlight the limitations of using time to PSA failure as a clinical indicator of androgen deprivation efficacy. We propose an alternative indicator, namely a treatment efficacy index, for patients with castration resistant disease, to identify who would benefit most from enhanced androgen deprivation. Conclusions: A critical challenge in prostate cancer therapeutics is quantifying the relationship between serum PSA and tumor burden. Our results underscore the potential of mathematical modeling in understanding the limitations of serum PSA as a prognostic indicator. Finally, we provide a means of augmenting PSA time-courses in the diagnostic process, with changes in intra-tumoral vascularity and vascular architecture .
Abstract Background: The purpose of this meta-analysis was to look at the relationship between hypernatremia and mortality in COVID-19 patients. Methods: We searched the PubMed, Web of science, Embase and Cochrane databases for articles published from the inception of the database until August 27, 2022. Three researchers reviewed the literature, retrieved data, and assessed the quality of the literature, respectively. A meta-analysis was performed using State 17 software to assess the value of the effect of hypernatremia on mortality in patients with new coronavirus pneumonia. Results: A total of 9 publications was finally included in this study, including a total of 11,801 patients with COVID-19, including 1,278 in the hypernatremia group and 10,523 in the normonatremia group. Meta-analysis showed that hypernatremia was associated with mortality in patients with COVID-19 [OR = 4.15, 95% CI (2.95-5.84), P = 0.002, I² = 66.7%] with a sensitivity of 0.36 [0.26, 0.48] and a specificity of 0.88 [ 0.83, 0.91]. The posterior probability of mortality was 42% in patients with COVID-19 hypernatremia and 15% in patients who did not have COVID-19 hypernatremia. Conclusion: According to available data, hypernatremia is associated with death in patients with COVID-19.
A new heterotrophic dinoflagellate, Protoperidinium vietnamicum sp. nov. was described from the coastal waters of Viet Nam. It is characterized by its elongation, pentagonal to pyriform body in ventral or dorsal view, and moderately dorsoventrally compressed. Epitheca is tapering into a robust apical horn and shorter than antapical horns. Cingulum equatorial, slightly descending. Sulcus wide, shallow, and slightly oblique. Plate 1’ is ortho-type, and intercalary 2a and 3a plates are pentagonal. Plate 1a is quadrangular, and its area is approximately triple times smaller than plate 3a. A new combination is proposed, the Protoperidinium curvicorne (Böhm) comb. nov. has distinct morphological features from other members of the section Oceanica. It presents a large cell-sized species with a round, broad body, and strong dorsoventral compression. The epitheca abruptly transitions into a slender apical horn strongly tilted towards the ventral side. Cingulum is narrow, shallow, descending, and strongly inclined relative to the equatorial plane of the cell. The plate 1’ is ortho-type, and 2а and 3а are asymmetrical and pentagonal. Both species are provided with detailed descriptions and are illustrated with line drawings, as well as with light microscopy images and SEM micrographs. In-depth discussion and comparison with similar species are presented.
The present study reports the discovery of Fimbristylis pachmarhiensis (Cyperaceae) as a new species from central India. The specimens were collected from the Pachmarhi hills located in Madhya Pradesh.To aid in the accurate identification of this species, an extensive taxonomic description, accompanied by photographic illustrations, a comparative analysis with similar species, and supplementary notes have been included. These comprehensive details serve to enhance our understanding and recognition of this newly discovered plant species.
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with unclear etiology. Clinical manifestations include dyspnea and nonproductive cough. Lung transplantation is the only cure, while Pirfenidone and Nintedanib are FDA-approved drugs for slowing disease progression. However, Saracatinib shows greater efficacy. This literature review assesses the safety and efficacy of IPF treatments, focusing on Pirfenidone and Nintedanib, which preserve lung function and reduce fibrosis and inflammation. We also evaluate emerging treatments such as saracatinib, pamrevlumab, pentraxin-2, BI 1015550, ziritaxestat, PBI-4050, bexotegrast, BMS-986020, TD 139, dasatinib, quercetin, and etanercept. Additional research is needed to explore the therapeutic potential and address gaps in IPF management, including exacerbation and associated pulmonary hypertension (PH). Immunosuppressive agents are used to manage IPF exacerbations, while PH is a recognized comorbidity. Clinical trials, PULSAR and SPECTRA, investigate Sotatercept as a potential PH treatment for IPF patients, showing promising results.
Malaxis ybytui is proposed as a new species from the wetlands of the Campos de Altitude of the Atlantic Rainforest of South Brazil. It is described, illustrated, and compared with other similar species. The new species is recognised by its flat to slightly conduplicate leaves, densely congested inflorescence with small flowers bearing free lateral sepals and four cavities in the lip. It is similar to Malaxis cipoensis and Malaxis sertulifera, being distinguished by its vegetative and floral morphology. The species is found in the mountain’s hillside about 1500m elevation in the Serra do Araçatuba\Papanduva mountain chain. Due to the high degree of endemism in this environment, the few collection records and the anthropic pressure in the region, we infer that the species is Critically Endangered (CR).
To determine distinct phenotype groups in patients with idiopathic inflammatory myopathy (IIM), and to identify the differences of clinical characteristics, laboratory findings, and the long-term outcomes in patients with antisynthetase syndrome (ASS) of different anti-aminoacyl-tRNA synthetase (ARS) antibodies. Methods: We enrolled retrospectively 280 patients with IIM, and the clinical characteristics and laboratory findings were collected. Additionally, multivariate COX regression analysis was performed to identify indicators of poor prognosis in patients with ASS. Results: 119 ASS and 161 non-ASS patients were identified in 280 patients with IIM, the occurrence rates of ILD, RP-ILD, pulmonary symptoms, arthritis, triad and mechanic’s hands with ASS group were more prevalent than non-ASS group ( p＜0.05). Among 119 patients with ASS, the highest incidence of RP-ILD occurred in the PL12 group (36.4%). There was clinical significance of statistical differences in arthritis, myositis, mechanic’s hands, triad, shawl sign, v sign, and Raynaud’s phenomenon among the 4 subgroups ( p＜0.05). At the same time, the individuals in the positive anti-Jo1 antibody group were more likely to exhibit arthritis, myositis, mechanic’s hands, triad and, v sign than the negative anti-Jo1 antibody group in patients with ASS, furthermore, statistically more prevalent ( p＜0.05). According to the multivariate COX regression analysis, mechanic’s hands, ANA, and ILD were independent risk factors for poor prognosis in patients with ASS ( p<0.001, p=0.026, and p<0.001, respectively). V sign was an independent protective factor for good prognosis in patients with ASS ( p=0.026). Conclusions: When clinical characteristics including pulmonary symptoms, arthritis, mechanic’s hands, ANA, along with ILD appear, clinicians should be on the alert for the occurrence of ASS in patients with IIM
Viola pendulipedunculata (Violaceae), a new species from Baiwan Nature Reserve of Guangdong Province in China, is described and illustrated. The new species is most similar to V. nanlingensis morphologically, but it can be easily distinguished by its narrowly oblong anterior petals (vs. spatulate anterior petals), curved and drooping peduncles (vs. erect peduncles), and seed with obvious elaiosome (vs. inconspicuous elaiosomes) and the whole plant. Our phylogenetic analysis, based on ITS sequences, confirms that the new species belongs to V. sect. Diffusae, and mostly related to V. yunnanensis in the phylogeny.
Collecting expeditions carried out in the Zamboanga Peninsula of western Mindanao led to the rediscovery of Thottea philippinensis, previously known only by a single collection made 93 years ago in the Philippines. Thus, in this paper, we provide descriptions, comments on the affinities among closely related species, an updated geographical distribution, habitat information, conservation assessment, and the first-ever published photos of living T. philippinensis in the wild. Additionally, we include notes on confirming the occurrence of T. tomentosa in the Philippine archipelago.
Gynodioecy has been identified to occur in the herbaceous polycarpic Origanum vulgare ssp. gracile growing in Tajikistan and is here described in detail for the first time. The investigated populations of O. vulgare ssp. gracile form two types of flowers, perfect and pistillate, on different individuals. In pistillate flowers, stamens are represented by staminodes. The size of many parts of the corolla and androecium of perfect flowers is significantly larger than in pistillate flowers. Four criteria have been identified that make it possible to reliably distinguish flowers of different sexual forms: the size of the corolla and its parts, the difference between calyx tube length versus corolla tube length, the position of the anthers, and the rate of development of stamens. Perfect flowers are characterized by strictly pronounced protandry. According to the pollen/ovule ratio (from 825 to 953), O. vulgare ssp. gracile is facultatively xenogamous. Hermaphrodites predominated (from 58.9% to 76.2%) in five of the investigated populations. The frequency of females in O. vulgare ssp. gracile was shown to be most dependent on annual precipitation (Bio12). Finally, we discuss the presence and distribution of gynodioecy within the genus Origanum and its adaptive significance for the existence of populations of O. vulgare ssp. gracile.
Objective B cell activating factor (BAFF) is a key regulator of Primary Sjögren’s Syndrome (pSS), which is characterized by B lymphocyte hyperactivity. BAFF is also known as TNF ligand superfamily member 13B (TNFSF13B). This study aimed to explore whether five single nucleotide polymorphisms (SNPs) of the TNFSF13B gene (rs9514827, rs1041569, rs9514828, rs1224141, and rs12583006) are related to pSS susceptibility. Methods We searched Pubmed, Cochrane, Elsevier, Web of Science, CNKI, CQVIP, and WanFang databases (up to January 2023). In a population with pSS, the odds ratios (ORs) with 95% confidence intervals (CIs) of genotypes and each allele were provided to investigate relationships between the polymorphisms of the BAFF (TNFSF13B) gene and pSS. Results The meta-analysis in question contains three studies. In the group of pSS patients and randomly selected health controls (HCs), there was a statistically significant relationship between rs1041569 and rs12583006 and pSS susceptibility, respectively. In fixed models, there were statistical differences in pSS patients and randomly chosen HCs. Conclusions There were relationships of rs1041569 and rs12583006 in the pSS group and HC group. BAFF(TNFSF13B) genes, particularly rs1041569 and rs12583006, were related to pSS susceptibility in pSS patients.
Background: Maintenance doses for AIT have been recommended for at least 3 years, little data on long-term efficacy is available depending on AIT duration. To show sustained efficacy 10 years after completion of treatment with depigmented-polymerized house dust mite (dpg-pol HDM) allergen extract in adults with asthma and/or rhinoconjunctivitis. Methods: Patients included in a double-blind placebo-controlled AIT study with dpg-pol HDM allergen extract were reviewed at completion of the perennial treatment and 10 years later (10y-FU). Change in symptom and rescue medication score was the primary objective. Visual analogue scale, asthma control test (ACT) and degree of disease control were secondary objectives. A comparative analysis between patients who underwent treatment for < 3 years and ≥ 3 years was performed. Results: Data from 31 patients (mean age 38 years) were available at 10y-FU. All had asthma and 29 had rhinoconjunctivitis at baseline. Twenty-three patients were treated ≥ 3y and 8 for < 3y. Seventeen (55%) patients were asymptomatic at completion AIT completion, with significant differences for nasal, conjunctival and bronchial symptoms (p<0.0001) compared to baseline only in patients treated ≥3y. Nine (52.9%) patients remained completely asymptomatic at 10yFU , all were treated for ≥ 3 years. Moreover, significant reduction in the number of patients with rhinitis (p=0.0117), conjunctivitis (p<0.0001) and bronchial (p=0.0005) symptoms was observed at 10y-FU compared to baseline only in the ≥3y treated. Ten (32.3%) patients didn´t require any rescue medication at 10y-FU, all had been treated for ≥ 3y. ACT at 10y-FU showed a good control of asthma (median 23.5; 95% IC[22.0, 25.0]). No significant differences were observed between VAS at end of treatment compared to VAS at 10y-FU. Conclusions: Sustained clinical efficacy is achieved 10 years after completion of depigmented-polymerized HDM, however these findings were observed only if patients are treated for at least 3 years.