Berntsengibbs1162

Niemann-Pick type C (NPC, MIM #257220) is a neuro-visceral disease, caused predominantly by pathogenic variants in the NPC1 gene. Here we studied patients with clinical diagnosis of NPC but inconclusive results regarding the molecular analysis.

We used a Next-Generation Sequencing (NGS)-panel followed by cDNA analysis. Latter, we used massively parallel single-cell RNA-seq (MARS-Seq) to address gene profiling changes and finally the effect of different variants on the protein and cellular levels.

We identified novel variants and cDNA analysis allowed us to establish the functional effect of a silent variant, previously reported as a polymorphism. We demonstrated that this variant induces the skipping of exon 11 leading to a premature stop codon and identified it in NPC patients from two unrelated families. MARS-Seq analysis showed that a number of upregulated genes were related to the unfolded protein response (UPR) and endoplasmic reticulum (ER) stress in one specific patient. Also, for all analyzed variants, the NPC1 protein was partially retained in the ER.

We showed that the NPC1 silent polymorphism (p.V562V) is a disease-causing variant in NPC and that the UPR is upregulated in an NPC patient.

We showed that the NPC1 silent polymorphism (p.V562V) is a disease-causing variant in NPC and that the UPR is upregulated in an NPC patient.

To prospectively assess acute differences in patient-reported outcomes in bowel and urinary domains between intensity-modulated radiotherapy (IMRT) and proton beam therapy (PBT) for prostate cancer.

Bowel function (BF), urinary irritative/obstructive symptoms (UO), and urinary incontinence (UI) domains of EPIC-26 were collected in patients with T1-T2 prostate cancer receiving IMRT or PBT at a tertiary cancer center (2015-2018). Mean changes in domain scores were analyzed from pretreatment to the end of and 3months post-radiotherapy for each modality. A clinically meaningful change was defined as a score change >50% of the baseline standard deviation.

A total of 157 patients receiving IMRT and 105 receiving PBT were included. There were no baseline differences in domain scores between cohorts. At the end of radiotherapy, there was significant and clinically meaningful worsening of BF and UO scores for patients receiving either modality. In the BF domain, the IMRT cohort experienced greater decrement (-13.0 vs -6.7, P<.01), and had a higher proportion of patients with clinically meaningful reduction (58.4% vs 39.5%, P=.01), compared to PBT. At 3months post-radiotherapy, the IMRT group had significant and clinically meaningful worsening of BF (-9.3, P<.001), whereas the change in BF score of the PBT cohort was no longer significant or clinically meaningful (-1.2, P=.25). CTPI-2 supplier There were no significant or clinically meaningful changes in UO or UI 3months post-radiotherapy.

PBT had less acute decrement in BF than IMRT following radiotherapy. There was no difference between the two modalities in UO and UI.

PBT had less acute decrement in BF than IMRT following radiotherapy. There was no difference between the two modalities in UO and UI.Second primary malignancy (SPM) ranks the second leading cause of death in patients with head and neck cancer (HNC), while studies exploring the risk factors for SPM are limited. To clarify this, we investigated the relationship between the chemotherapy and SPM using the Surveillance, Epidemiology, and End Results (SEER) database. 11 345 patients initially diagnosed with HNC between 1998 and 2016 were selected from the SEER database. First, these patients were divided into two groups according to chemotherapy or not. With Fine and Gray model, the subdistribution hazard ratio (sHR) of chemotherapy was calculated based on Propensity Score Matching (PSM). Second, the 11 345 cases were randomized into a training set and a validation set. Based on the training set, the different cumulative incidence of SPMs between the patients with and without chemotherapy was estimated respectively in the high- and low-risk group according to the scores derived from a nomogram. Chemotherapy was negatively correlated to the SPMs (sHR 0.847, 95% CI 0.733-0.977, P = .023) by conducting competing risk analysis. With chemotherapy, forest plots showed subgroups of squamous cell carcinoma (SCC, sHR 0.815, 95% CI 0.7-0.948, P = .008), 50-64 years old (sHR0.794, 95% CI 0.655-0.962, P = .019), male (sHR0.828, 95% CI 0.703-0.974, P = .023), and well/moderate histological grade (sHR0.828, 95% CI 0.688-0.996, P = .045) were negatively correlated to SPMs; the nomogram showed the high-risk population characterized as SCC, elder age, male, and well/moderate histological grade also tended to have lower incidence of SPMs (sHR 0.805, 95% CI 0.669-0.969, P = .022). Despite HNC patients with characteristics of SCC, increased age, male, and well/moderate histological grade had higher risk of a SPM, they were also more likely to be benefitted from chemotherapy to avoid it.Serology is a core component of the surveillance and management of viral zoonoses. Virus neutralization tests are a gold standard serological diagnostic, but requirements for large volumes of serum and high biosafety containment can limit widespread use. Here, focusing on Rabies lyssavirus, a globally important zoonosis, we developed a pseudotype micro-neutralization rapid fluorescent focus inhibition test (pmRFFIT) that overcomes these limitations. Specifically, we adapted an existing micro-neutralization test to use a green fluorescent protein-tagged murine leukaemia virus pseudotype in lieu of pathogenic rabies virus, reducing the need for specialized reagents for antigen detection and enabling use in low-containment laboratories. We further used statistical models to generate rapid, quantitative predictions of the probability and titre of rabies virus-neutralizing antibodies from microscopic imaging of neutralization outcomes. Using 47 serum samples from domestic dogs with neutralizing antibody titres estimated using the fluorescent antibody virus neutralization test (FAVN), pmRFFIT showed moderate sensitivity (78.79%) and high specificity (84.62%). Despite small conflicts, titre predictions were correlated across tests repeated on different dates both for dog samples (r = 0.93) and in a second data set of sera from wild common vampire bats (r = 0.72, N = 41), indicating repeatability. Our test uses a starting volume of 3.5 µl of serum, estimates titres from a single dilution of serum rather than requiring multiple dilutions and end point titration, and may be adapted to target neutralizing antibodies against alternative lyssavirus species. The pmRFFIT enables high-throughput detection of rabies virus-neutralizing antibodies in low-biocontainment settings and is suited to studies in wild or captive animals where large serum volumes cannot be obtained.