Hawleybek0310
The marketing approval, about ten years ago, of the first disease modulator for patients with cystic fibrosis harboring specific CFTR genotypes (~5% of all patients) brought new hope for their treatment. To date, several therapeutic strategies have been approved and the number of CFTR mutations targeted by therapeutic agents is increasing. Although these drugs do not reverse the existing disease, they help to increase the median life expectancy. However, on the basis of their CFTR genotype, ~10% of patients presently do not qualify for any of the currently available CFTR modulator therapies, particularly patients with splicing mutations (~12% of the reported CFTR mutations). Efforts are currently made to develop therapeutic agents that target disease-causing CFTR variants that affect splicing. This highlights the need to fully identify them by scanning non-coding regions and systematically determine their functional consequences. In this review, we present some examples of CFTR alterations that affect splicing events and the different therapeutic options that are currently developed and tested for splice switching.The daily removal of billions of apoptotic cells in the human body via the process of efferocytosis is essential for homeostasis. To allow for this continuous efferocytosis, rapid phenotypic changes occur in the phagocytes enabling them to engulf and digest the apoptotic cargo. In addition, efferocytosis is actively anti-inflammatory and promotes resolution. Owing to its ubiquitous nature and the sheer volume of cell turnover, efferocytosis is a point of vulnerability. Aberrations in efferocytosis are associated with numerous inflammatory pathologies, including atherosclerosis, cancer and infections. The recent exciting discoveries defining the molecular machinery involved in efferocytosis have opened many avenues for therapeutic intervention, with several agents now in clinical trials.It is vital for physicians and persons with chronic myeloid leukemia (CML) to accurately predict the likelihood of achieving a major molecular response (MMR) and a deep molecular response (DMR; at least MR4) at the start of imatinib-therapy, which could help in decision making of treatment goals and strategies. To answer this question, we interrogated data from 1369 consecutive subjects with chronic phase CML receiving initial imatinib-therapy to identify predictive co-variates. Subjects were randomly-assigned to training (n = 913) and validation (n = 456) datasets. Male sex, higher WBC concentration, lower haemoglobin concentration, higher percentage blood blasts and larger spleen size were significantly-associated with lower cumulative incidences of MMR and MR4 in training dataset. Using Fine-Gray model, we developed the predictive scoring systems for MMR and MR4 which classified subjects into the low-, intermediate- and high-risk cohorts with significantly-different cumulative incidences of MMR and MR4 with good predictive discrimination and accuracy in training and validation cohorts with high area under the receiver-operator characteristic curve (AUROC) values. These data may help physicians decide appropriateness of initial imatinib therapy.Drought is the most detrimental abiotic stress to sugarcane production. Nevertheless, transcriptomic analyses remain scarce for field-grown plants. Here we performed comparative transcriptional profiling of two contrasting sugarcane genotypes, 'IACSP97-7065' (drought-sensitive) and 'IACSP94-2094' (drought-tolerant) grown in a drought-prone environment. Physiological parameters and expression profiles were analyzed at 42 (May) and 117 (August) days after the last rainfall. The first sampling was done under mild drought (soil water potential of -60 kPa), while the second one was under severe drought (soil water potential of -75 kPa). Microarray analysis revealed a total of 622 differentially expressed genes in both sugarcane genotypes under mild and severe drought stress, uncovering about 250 exclusive transcripts to 'IACSP94-2094' involved in oxidoreductase activity, transcriptional regulation, metabolism of amino acids, and translation. Interestingly, the enhanced antioxidant system of 'IACSP94-2094' may protect photosystem II from oxidative damage, which partially ensures stable photochemical activity even after 117 days of water shortage. Moreover, the tolerant genotype shows a more extensive set of responsive transcription factors, promoting the fine-tuning of drought-related molecular pathways. These results help elucidate the intrinsic molecular mechanisms of a drought-tolerant sugarcane genotype to cope with ever-changing environments, including prolonged water deficit, and may be useful for plant breeding programs.It has been debated whether intensive selection for growth and carcass yield in pig breeding programmes can affect the size of internal organs, and thereby reduce the animal's ability to handle stress and increase the risk of sudden deaths. To explore the respiratory and circulatory system in pigs, a deep learning based computational pipeline was built to extract the size of lungs and hearts from CT-scan images. This pipeline was applied on CT images from 11,000 boar selection candidates acquired during the last decade. Further, heart and lung volumes were analysed genetically and correlated with production traits. Both heart and lung volumes were heritable, with h2 estimated to 0.35 and 0.34, respectively, in Landrace, and 0.28 and 0.4 in Duroc. Both volumes were positively correlated with lean meat percentage, and lung volume was negatively genetically correlated with growth (rg = - 0.48 ± 0.07 for Landrace and rg = - 0.44 ± 0.07 for Duroc). The main findings suggest that the current pig breeding programs could, as an indirect response to selection, affect the size of hearts- and lungs. The presented methods can be used to monitor the development of internal organs in the future.Activity-induced neurogenesis has been extensively studied in rodents but the lack of ante mortem accessibility to human brain at the cellular and molecular levels limits studies of the process in humans. Using cerebral spheroids derived from human induced pluripotent stem cells (iPSCs), we investigated the effects of 4-aminopyridine (4AP) on neuronal activity and associated neurogenesis. Our studies demonstrate that 4AP increases neuronal activity in 3-month-old cerebral spheroids while increasing numbers of new neurons and decreasing the population of new glial cells. We also observed a significant decrease in the expression of miR-135a, which has previously been shown to be decreased in exercise-induced neurogenesis. Predicted targets of miR-135a include key participants in the SMAD2/3 and BDNF pathways. Together, our results suggest that iPSC-derived cerebral spheroids are an attractive model to study several aspects of activity-induced neurogenesis.
Ultrasound (US) guided pulsed radiofrequency (PRF) therapy can be used on the greater occipital nerve (GON) in patients with chronic migraine (CM) who are unresponsive to conservative treatments. We aimed to demonstrate the change in pain intensity, duration of migraine episodes, frequency of attacks, migraine disability, depression, and sleep disturbance scores before and after treatment in patients with CM who underwent US-guided GON PRF and the effectiveness of treatment.
According to the International Classification of Headache Disorders III beta version diagnostic criteria, 25 of 43 patients with CM whom treated with GON PRF were included in the study. The Migraine Disability Assessment Scale (MIDAS), Beck Depression Inventory (BDI), Pittsburgh Sleep Quality Index (PSQI), and a visual analog scale (VAS) were used on patients before GON PRF treatment and at post treatment months 1 and 3.
The median duration and number of migraine episodes in the post-interventional 1st month and 3rd month were significantly shorter and fewer compared with the pre-intervention period (p < 0.001). PF-6463922 In the comparison with the pre-intervention values, all of the scoring concepts, namely the MIDAS, VAS, BDI, and PSQI, revealed a significant drop in the postintervention 1st and 3rd month (p < 0.001).
In this study, we observed that US-guided GON PRF therapy applied at the proximal (C2) level was a safe and effective treatment option. With GON PRF, we observed a decrease in pain intensity, pain frequency, and duration of episodes, and an improvement in depression symptoms, migraine disability, and sleep disorder scores accompanying chronic migraine.
In this study, we observed that US-guided GON PRF therapy applied at the proximal (C2) level was a safe and effective treatment option. With GON PRF, we observed a decrease in pain intensity, pain frequency, and duration of episodes, and an improvement in depression symptoms, migraine disability, and sleep disorder scores accompanying chronic migraine.We report a case of a 73-year-old woman affected by Lemmel's syndrome, a rare type of obstructive jaundice caused by a periampullary duodenal diverticulum. The patient was admitted to the Emergency Department for pneumonia associated with mild epigastric pain and vomiting. While hospitalized for antibiotic treatment, the appearance of jaundice led us to discover a periampullary duodenal diverticulum by endoscopy and CT scan. The jaundice was successfully managed endoscopically with removal of food debris from the diverticulum.
Pancreatic cancer (PC) is the most lethal malignant tumor, with average survival period of about 10 months. C-X-C ligand 5 (CXCL5), an important chemokine for immune cell accumulation in tumor tissues, has been reported to be involved in a variety of human cancers. However, the exact role of CXCL5 in PC progression has not been well defined.
The expression of CXCL5 in PC was analyzed based on online databases and clinical specimens immunohistochemical staining, and Western blotting of CXCL5 in PC cell lines and patient samples. The correlation between CXCL5 expression and prognosis in PC was explored. The role of CXCL5 in PC was investigated through in vitro and in vivo experiments.
The expression of CXCL5 was significantly increased in PC tissues compared with that in pancreas tissues, and CXCL5 high expression predicts poor prognosis in PC patients. Further analyses demonstrated that overexpression of CXCL5 in PC cells was positively related to higher proliferation rate, higher migration ability, and higher EMT markers including SNAI2 and TWIST1 of tumor cells in vitro. Consistently, the knockdown of CXCL5 in PC cells harmed the proliferation rate, migration ability, and expression of EMT indexes of tumor cells in vitro. Importantly, knockdown of CXCL5 inhibited the growth of xenograft tumors in vivo.
CXCL5 high expression predicts poor prognosis in PC patients. CXCL5 promotes PC cell growth and EMT process. Inhibition of CXCL5 may be a potential therapeutic approach for PC.
CXCL5 high expression predicts poor prognosis in PC patients. CXCL5 promotes PC cell growth and EMT process. Inhibition of CXCL5 may be a potential therapeutic approach for PC.
The description of the clinical presentation of celiac disease (CeD) has usually come from studies at referral centers. Data about CeD presentation in the community are sparse.
We aim to describe the clinical presentation of patients with biopsy-proven CeD at a community-based adult gastroenterology practice and compare it to a referral center.
We performed a retrospective study of two cohorts of patients diagnosed with CeD between 2000-2007 (n = 117) and 2013-2016 (n = 91) in a community practice, and a third cohort (n = 188) diagnosed between 2000 and 2007 in a tertiary referral center. The clinical presentation, body mass index, tissue-transglutaminase levels, DEXA scan, vitamin D levels, and vaccine recommendations were assessed.
Celiac disease presentation changed over time in the two community cohorts. Recently, fewer patients presented with diarrhea and anemia, but constipation and neurologic symptoms were more common. The most recent cohort had a higher proportion of patients who were overweight or obese than the first cohort.
