This study aimed to determine the prevalence of immediate posttransplant hyperglycemia and new onset diabetes after renal transplantation (NODAT). It also aims at answering whether posttransplant ...hyperglycemia
is a risk factor for future development of NODAT.
A retrospective study was conducted among patients undergoing kidney transplantation under a single surgical unit in a tertiary care hospital in the past 5 years. All known patients with diabetes were excluded from the study. Immediate postoperative hyperglycemia was defined as random blood sugar (RBS) ≥200 mg/dl or requirement of insulin. NODAT was defined as fasting plasma glucose ≥126 mg/dl or RBS ≥200 mg/dl or if the patient is receiving therapy for glycemic control at 6 weeks or 3 months posttransplantation.
The study population included 191 patients. The overall prevalence of posttransplant hyperglycemia and NODAT was 31.4% and 26.7%, respectively. NODAT developed in 28 patients (46.7%) of those who had posttransplant hyperglycemia. Thus, posttransplant hyperglycemia was associated with a fourfold increased risk of NODAT (
= 0.000). Posttransplant hyperglycemia was associated with increased infections (
= 0.04) and prolonged hospital stay (
= 0.0001). Increased age was a significant risk factor for NODAT (
= 0.000), whereas gender, acute rejection episodes, cadaveric transplant, hepatitis C virus status, human leukocyte antigen mismatch, and high calcineurin levels were not significantly associated with the future development of NODAT.
The significant risk of NODAT posed by posttransplant hyperglycemia makes it prudent to follow up these patients more diligently in a resource-limited setting wherein routine monitoring in all patients is cumbersome.
Cell-free DNA (cfDNA) from plasma offers easily obtainable material for KRAS mutation analysis. Novel, multiplex, and accurate diagnostic systems using small amounts of DNA are needed to further the ...use of plasma cfDNA testing in personalized therapy.
Samples of 16 ng of unamplified plasma cfDNA from 121 patients with diverse progressing advanced cancers were tested with a KRASG12/G13 multiplex assay to detect the seven most common mutations in the hotspot of exon 2 using droplet digital polymerase chain reaction (ddPCR). The results were retrospectively compared to mutation analysis of archival primary or metastatic tumor tissue obtained at different points of clinical care.
Eighty-eight patients (73%) had KRASG12/G13 mutations in archival tumor specimens collected on average 18.5 months before plasma analysis, and 78 patients (64%) had KRASG12/G13 mutations in plasma cfDNA samples. The two methods had initial overall agreement in 103 (85%) patients (kappa, 0.66; ddPCR sensitivity, 84%; ddPCR specificity, 88%). Of the 18 discordant cases, 12 (67%) were resolved by increasing the amount of cfDNA, using mutation-specific probes, or re-testing the tumor tissue, yielding overall agreement in 115 patients (95%; kappa 0.87; ddPCR sensitivity, 96%; ddPCR specificity, 94%). The presence of ≥ 6.2% of KRASG12/G13 cfDNA in the wild-type background was associated with shorter survival (P = 0.001).
Multiplex detection of KRASG12/G13 mutations in a small amount of unamplified plasma cfDNA using ddPCR has good sensitivity and specificity and good concordance with conventional clinical mutation testing of archival specimens. A higher percentage of mutant KRASG12/G13 in cfDNA corresponded with shorter survival.
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Normal mode analysis of stability of shear flows of inviscid, incompressible fluids in channels with variable cross section and with a free upper surface is undertaken. Some general analytical ...results are obtained for basic flows with smooth velocity profiles in channels with smooth topography function. A Kelvin-Helmholtz instability study in a channel with constant topography function is also analyzed.
The stability problem of inviscid incompressible stratified shear flows in sea straits of arbitrary cross sections is formulated without the Boussinesq approximation. Series solutions of the ...stability equation are found by the method of Frobenius and these solutions are used to study the existence of neutral modes when the Richardson number is larger than one quarter. The energy aspect of the problem is studied by discussing the role of the Reynolds stress and its variation in the vertical direction for both unstable modes and neutral modes adjacent to the unstable modes. The interfacial conditions at layers of discontinuity of the basic velocity, density or topography are derived and these are used in the study of instability of two examples of basic flows.
Growth data of Salmonella in chicken were collected at several isothermal conditions (10, 15, 20, 25, 28, 32, 35, 37, 42, and 45 °C) and were then fitted into primary models, namely the logistic ...model, modified Gompertz model and Baranyi model. Measures of goodness-of-fit such as mean square error, pseudo-R2, -2 log likelihood, Akaike's information, and Sawa's Bayesian information criteria were used for comparison for these primary models. Based on these criteria, modified Gompertz model described growth data the best, followed by the Baranyi model, and then the logistic model. The maximum growth rates obtained from each primary model were then modeled as a function of temperature using the modified Ratkowsky model. Pseudo-R2 values for this secondary model describing growth rate obtained from Baranyi, modified Gompertz, and logistic models were 0.999, 0.980, and 0.990, respectively. Mean square error values for corresponding models were 0.0002, 0.0008, and 0.0009, respectively. Both measures clearly show that the Baranyi model performed better than the modified Gompertz model or the logistic model.
The objective of this study is to identify the association between linc-ROR genetic variants and oral squamous cell carcinoma tumorigenesis.
Four genetic variants of linc-ROR (rs6420545, rs4801078, ...rs1942348, and rs9636089) were analyzed in 178 OSCCs and 191 controls of the South Indian population by PCR amplification followed by restriction digestion. In addition, we examined whether these variants alter linc-ROR expression levels and the progression of OSCC.
The frequency of linc-ROR rs6420545 and rs4801078 genotypes were significantly associated with advanced tumor grade (>2) (p = 0.002 and p = 0.048), and nodal metastasis (p = 0.001 and p = 0.019), respectively. We observed a significant association of rs6420545 specifically in the over-dominant model OR 1.77 (95%CI; 1.17–2.68); p = 0.006 and rs9636089 in dominant model OR 2.17 (95%CI; 1.06 – 4.46); p = 0.03, and allelic model OR 2.26 (95%CI; 1.13 – 4.53) p = 0.02, respectively. Further, significant upregulation of linc-ROR (p = 0.005) was observed in our cohort, consistent with the HNSCC TCGA dataset (p < 0.0001).
Our findings suggest that the linc-ROR genetic variants could contribute to the metastasis and progression mainly in the late event of tumorigenesis of OSCCs and these variants could be useful in the precision therapeutic management of this cancer particularly in prognosis.
•Linc-ROR was significantly overexpressed in our study and HNSCC TCGA dataset.•Variants rs6420545 and rs4801078 associated with late tumorigenic events.•These SNPs are frequent in high grade, and nodal positive tumors.•rs6420545 and rs9636089 showed a significant association in genetic models.
Selpercatinib (LOXO-292) and pralsetinib (BLU-667) are highly potent RET-selective protein tyrosine kinase inhibitors (TKIs) for treating advanced RET-altered thyroid cancers and non-small-cell lung ...cancer (NSCLC). It is critical to analyze RET mutants resistant to these drugs and unravel the molecular basis to improve patient outcomes.
Cell-free DNAs (cfDNAs) were analyzed in a RET-mutant medullary thyroid cancer (MTC) patient and a CCDC6-RET fusion NSCLC patient who had dramatic response to selpercatinib and later developed resistance. Selpercatinib-resistant RET mutants were identified and cross-profiled with pralsetinib in cell cultures. Crystal structures of RET-selpercatinib and RET-pralsetinib complexes were determined based on high-resolution diffraction data collected with synchrotron radiation.
RETG810C/S mutations at the solvent front and RETY806C/N mutation at the hinge region were found in cfDNAs of an MTC patient with RETM918T/V804M/L, who initially responded to selpercatinib and developed resistance. RETG810C mutant was detected in cfDNAs of a CCDC6-RET-fusion NSCLC patient who developed acquired resistance to selpercatinib. Five RET kinase domain mutations at three non-gatekeeper residues were identified from 39 selpercatinib-resistant cell lines. All five selpercatinib-resistant RET mutants were cross-resistant to pralsetinib. X-ray crystal structures of the RET-selpercatinib and RET-pralsetinib complexes reveal that, unlike other TKIs, these two RET TKIs anchor one end in the front cleft and wrap around the gate wall to access the back cleft.
RET mutations at the solvent front and the hinge are resistant to both drugs. Selpercatinib and pralsetinib use an unconventional mode to bind RET that avoids the interference from gatekeeper mutations but is vulnerable to non-gatekeeper mutations.
•Resistance to selpercatinib and pralsetinib are found at the solvent front and hinge sites of the RET kinase domain.•The identified selpercatinib-resistant RET mutants are cross-resistant to pralsetinib.•Selpercatinib and pralsetinib use an unprecedented binding mode to dock into the RET kinase.•The new kinase inhibitor binding mode avoids the interference from gatekeeper mutations but remains vulnerable to non-gatekeeper mutations.
Emerging efficacy data have led to the emergency use authorization or approval of COVID-19 vaccines in several countries worldwide. Most trials of COVID-19 vaccines excluded patients with active ...malignancies, and thus data on the safety, tolerability and efficacy of the vaccines in patients with cancer are currently limited. Given the risk posed by the COVID-19 pandemic, decisions regarding the use of vaccines against COVID-19 in patients participating in trials of investigational anticancer therapies need to be addressed promptly. Patients should not have to choose between enrolling on oncology clinical trials and receiving a COVID-19 vaccine. Clinical trial sponsors, investigators and treating physicians need operational guidance on COVID-19 vaccination for patients with cancer who are currently enrolled or might seek to enrol in clinical trials. Considering the high morbidity and mortality from COVID-19 in patients with cancer, the benefits of vaccination are likely to far outweigh the risks of vaccine-related adverse events. Herein, we provide operational COVID-19 vaccine guidance for patients participating in oncology clinical trials. In our perspective, continued quality oncological care requires that patients with cancer, including those involved in trials, be prioritized for COVID-19 vaccination, which should not affect trial eligibility.
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