The lung is home to a dynamic microbial population crucial to modulating immune balance. Interest in the role of the lung microbiota in disease pathogenesis and treatment has exponentially increased. In lung cancer, early studies suggested an important role of dysbiosis in tumor initiation and progression. These results have helped accelerate research into the lung microbiota as a potential diagnostic marker and therapeutic target. Microbiota signatures could represent diagnostic biomarkers of early-stage disease. Lung microbiota research is in its infancy with a limited number of studies and only single-center studies with a significant methodological variation. Large, multicenter longitudinal studies are needed to establish the clinical potential of this exciting field.
The intestinal barrier is a complex structure that not only regulates the influx of luminal contents into the systemic circulation but is also involved in immune, microbial, and metabolic homeostasis. Evidence implicating disruption in intestinal barrier functions in the development of many systemic diseases, ranging from non-alcoholic steatohepatitis to autism, or systemic complications of intestinal disorders has increased rapidly in recent years, raising the possibility of the intestinal barrier as a potential target for therapeutic intervention to alter the course and mitigate the complications associated with these diseases. In addition to the disease process being associated with a breach in the intestinal barrier functions, patients with hematologic and oncologic diseases are particularly at high risks for the development of increased intestinal permeability, due to the frequent use of broad-spectrum antibiotics and chemoradiation. They also face a distinct challenge of being intermittently severely neutropenic due to treatment of the underlying conditions. In this review, we will discuss how hematologic and oncologic diseases are associated with disruption in the intestinal barrier and highlight the complications associated with an increase in the intestinal permeability. We will explore methods to modulate the complication. To provide a background for our discussion, we will first examine the structure and appraise the methods of evaluation of the intestinal barrier.
Introduction: Homozygous deletion of MTAP upregulates de novo synthesis of purine (DNSP) and increases the proliferation of neoplastic cells. This increases the sensitivity of breast cancer cells to DNSP inhibitors such as methotrexate, L-alanosine and pemetrexed. Materials and Methods: 7,301 cases of MBC underwent hybrid-capture based comprehensive genomic profiling (CGP). Tumor mutational burden (TMB) was determined on up to 1.1 Mb of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. Tumor cell PD-L1 expression was determined by IHC (Dako 22C3). Results: 208 (2.84%) of MBC featured MTAP loss. MTAP loss patients were younger (p = 0.002) and were more frequently ER− (30% vs. 50%; p < 0.0001), triple negative (TNBC) (47% vs. 27%; p < 0.0001) and less frequently HER2+ (2% vs. 8%; p = 0.0001) than MTAP intact MBC. Lobular histology and CDH1 mutations were more frequent in MTAP intact (14%) than MTAP loss MBC (p < 0.0001). CDKN2A (100%) and CDKN2B (97%) loss (9p21 co-deletion) were significantly associated with MTAP loss (p < 0.0001). Likely associated with the increased TNBC cases, BRCA1 mutation was also more frequent in MTAP loss MBC (10% vs. 4%; p < 0.0001). As for immune checkpoint inhibitors biomarkers, higher TMB >20 mut/Mb levels in the MTAP intact MBC (p < 0.0001) and higher PD-L1 low expression (1-49% TPS) in the MTAP loss MTAP (p = 0.002) were observed. Conclusions: MTAP loss in MBC has distinct clinical features with genomic alterations (GA) affecting both targeted and immunotherapies. Further efforts are necessary to identify alternative means of targeting PRMT5 and MTA2 in MTAP-ve cancers to benefit from the high-MTA environment of MTAP-deficient cancers.
Minimal residual disease (MRD) assessment using peripheral blood instead of bone marrow aspirate/biopsy specimen or the biopsy of the cancerous infiltrated by lymphoid malignancies is an emerging technique with enormous interest of research and technological innovation at the current time. In some lymphoid malignancies (particularly ALL), Studies have shown that MRD monitoring of the peripheral blood may be an adequate alternative to frequent BM aspirations. However, additional studies investigating the biology of liquid biopsies in ALL and its potential as an MRD marker in larger patient cohorts in treatment protocols are warranted. Despite the promising data, there are still limitations in liquid biopsies in lymphoid malignancies, such as standardization of the sample collection and processing, determination of timing and duration for liquid biopsy analysis, and definition of the biological characteristics and specificity of the techniques evaluated such as flow cytometry, molecular techniques, and next generation sequencies. The use of liquid biopsy for detection of minimal residual disease in T-cell lymphoma is still experimental but it has made significant progress in multiple myeloma for example. Recent attempt to use artificial intelligence may help simplify the algorithm for testing and may help avoid inter-observer variation and operator dependency in these highly technically demanding testing process.
Background: COronaVIrus Disease 2019 (COVID-19) has been observed to be associated with a hypercoagulable state. Intracardiac thrombosis is a serious complication but has seldom been evaluated in COVID-19 patients. We assessed the incidence, associated factors, and outcomes of COVID-19 patients with intracardiac thrombosis. Methods: COVID-19 inpatients during 2020 were retrospectively identified from the national inpatient sample (NIS) database, and data retrieved regarding clinical characteristics, intracardiac thrombosis, and adverse outcomes. Multivariable logistic regression was performed to identify the clinical factors associated with intracardiac thrombosis and in-hospital mortality and morbidities. Results: A total of 1,683,785 COVID-19 inpatients were identified in 2020 from NIS, with a mean age of 63.8 ± 1.6 years, and 32.2% females. Intracardiac thrombosis was present in 0.001% (1,830) patients. Overall, in-hospital outcomes include all-cause mortality 13.2% (222,695/1,683,785), cardiovascular mortality 3.5%, cardiac arrest 2.6%, acute coronary syndrome (ACS) 4.4%, heart failure 16.1%, stroke 1.3% and acute kidney injury (AKI) 28.3%. The main factors associated with intracardiac thrombosis were a history of congestive heart failure and coagulopathy. Intracardiac thrombosis was independently associated with a higher risk of in-hospital all-cause mortality (OR: 3.32, 95% CI: 2.42-4.54, p<0.001), cardiovascular mortality (OR: 2.95, 95% CI: 1.96-4.44, p<0.001), cardiac arrest (OR: 2.04, 95% CI: 1.22-3.43, p=0.006), ACS (OR: 1.62, 95% CI: 1.17-2.22, p=0.003), stroke (OR: 3.10, 95% CI: 2.11-4.56, p<0.001), and AKI (OR: 2.13 95% CI: 1.68-2.69, p<0.001), but not incident heart failure (p=0.27). Conclusion: Although intracardiac thrombosis is rare in COVID-19 inpatients, its presence was independently associated with higher risks of in-hospital mortality and most morbidities. Prompt investigations and treatments for intracardiac thrombosis are warranted when there is a high index of suspicion and a confirmed diagnosis respectively.
Voxelotor is an allosteric haemoglobin (Hb) modulator that binds covalently and reversibly to Hb alpha chain to facilitate improved Hb-O 2 affinity and arterial oxygen. It, therefore, reduces the susceptibility of erythrocytes carrying Haemoglobin S to sickle. In this study, we have used GBT1118, an analog of voxelotor, to treat male Townes sickle cell disease (SCD) mice to investigate whether the Hb modulator could attenuate the intestinal pathophysiologic changes associated with SCD. Compared with mice fed with control chow, GBT1118-treated mice showed improvement in the intestinal pathophysiology. These mice exhibited improved small intestinal barrier functions, reduced intestinal microbial density, reduced enterocyte injury, lower serum lipopolysaccharides and smaller spleens. These improvements were observed after only 3 weeks of GBT1118 treatment. Benefits were also observed after experimentally-induced vaso-occlusive crisis (VOC). Recovery from the VOCinduced changes was faster in mice that were treated with GBT1118. The improved small intestinal barrier function was associated with higher expression of genes encoding enterocyte E-cadherin, JAM-A, ZO-1, MUC-2 and occludin while the lower intestinal microbial density associated with higher expression of genes encoding the antimicrobial peptides defensin-α 1 and defensin-α 4. Our findings provide the evidence to support the beneficial effects of GBT1118 in SCD-related intestinal pathophysiology.
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