Tag: pubmed

Cancer Med. 2022 Jun 23. doi: 10.1002/cam4.4971. Online ahead of print.

ABSTRACT

INTRODUCTION: New treatment strategies for advanced non-small-cell lung carcinoma (NSCLC) include synthetic lethality targets focused on protein arginine methyl transferases such as PRMT5 that exploit the impact of genomic loss of methylthioadenosine phosphorylase (MTAP).

METHODS: Twenty nine thousand three hundred seventy nine advanced NSCLC cases underwent hybrid-capture based comprehensive genomic profiling between June 1, 2018 and May 31, 2020. PD-L1 expression was determined by immunohistochemistry (Dako 22C3 PharmDx assay).

RESULTS: 13.4% (3928/29,379) NSCLC cases exhibited MTAP loss distributed in adenocarcinoma (59%), squamous cell carcinoma (22%), NSCLC not otherwise specified (16%), and 1% each for large-cell neuroendocrine, sarcomatoid, and adenosquamous carcinoma. Statistically significant differences in mitogenic driver alterations included more KRAS G12C mutations in MTAP-intact versus MTAP-lost (12% vs. 10%, p = 0.0003) and fewer EGFR short variant mutations in MTAP-intact versus MTAP-lost NSCLC (10% vs. 13%, p < 0.0001). Statistically significant differences in currently unforgettable genomic alterations included higher frequencies of TP53 (70% vs. 63%, p < 0.0001) and RB1 inactivation (10% vs. 2%, p < 0.0001) in MTAP-intact compared to MTAP-lost NSCLC. SMARCA4 inactivation (7% vs. 10%, p < 0.0001) was less frequent in MTAP-intact versus MTAP-lost NSCLC. Alterations in ERBB2, MET, ALK, ROS1, and NTRK1 did not significantly differ between the two groups. Predictors of immunotherapy efficacy were higher in MTAP-intact versus MTAP-lost NSCLC including tumor mutational burden (9.4 vs. 8.6 mut/Mb, p = 0.001) and low (30% vs. 28%, p = 0.01) and high PD-L1 (32% vs. 30%, p = 0.01) expression. Alterations in biomarkers potentially predictive of immune checkpoint inhibitor resistance (STK11, KEAP1, and MDM2) were similar in the two groups.

CONCLUSIONS: MTAP loss occurs in 13% of NSCLC, supporting the development of targeted therapies to exploit PRMT5 hyper-dependence. MTAP loss is accompanied by small differences in targeted and immunotherapy options which may impact future combination strategies.

PMID:35747993 | DOI:10.1002/cam4.4971

Curr Pharm Des. 2022 Jun 23. doi: 10.2174/1381612828666220623102537. Online ahead of print.

ABSTRACT

BACKGROUND AND PURPOSE: Cardio-cerebrovascular disease is an important public health challenge worldwide, and its complex etiology has not been elucidated fully. The study was to investigate the relationship between two common polymorphisms C677T and A1298C in the methylenetetrahydrofolate reductase (MTHFR) gene, baseline lipids and the lipid-lowering efficacy of simvastatin in a Chinese hyperlipidemic population.

METHODS: All participants were recruited from Anhui, China. By the extreme sampling method, we selected subjects with low response (n=108) and high response (n=106) based on their adjusted lipid-lowering response to simvastatin administrated for 8 consecutive weeks. Both MTHFR C677T and A1298C loci were genotyped by MALDI-TOF MS platform. Serum triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) levels were measured at baseline and after 8 weeks of oral 20 mg/d tablet of simvastatin.

RESULTS: Patients with the 677TT genotype had significantly higher baseline TC, HDL-C, and change in HDL-C (ΔHDL-C) levels after treatment than those with 677CC+CT genotypes (β = 0.207, P = 0.045; β = 0.182, P = 0.026; and β = 0.16, P = 0.002, respectively). Patients with 1298AC+CC genotypes had significantly higher baseline LDL-C and change in LDL-C (ΔLDL-C) levels (β = 0.276, P =0.043; β = 0.359, P = 0.025, respectively) than those with 1298AA genotype. We found statistical interactions between the two SNPs in association with baseline HDL-C (P for interaction = 0.034), TC (P for interaction = 0.069), and TG (P for interaction = 0.034). Baseline TC (P = 0.027) and HDL-C (P = 0.046) and change in HDL-C (P = 0.019) were different among those with the MTHFR A-T haplotype compared with A-C.

CONCLUSIONS: Our major findings suggest that both MTHFR C677T and A1298C polymorphisms could be important genetic determinants of lipid traits and drug efficacy of simvastatin. This will contribute to a better understanding of strategies for personalized medication in Chinese patients with dyslipidemia.

PMID:35747958 | DOI:10.2174/1381612828666220623102537

Rejuvenation Res. 2022 Jun 23. doi: 10.1089/rej.2022.0029. Online ahead of print.

ABSTRACT

Our previous study showed that the exchange of blood between heterochronic parabionts for 3 months did not rejuvenate the immune system of the old partners. Moreover, the young immune system became more aged and began to function according to the “old” principle. Does this “forced aging” affect all organism’s systems in this model? We checked the levels of corticosterone, testosterone, IGF-1, insulin, thyroxine in the blood of heterochronic parabionts but did not find significant changes compared to the age-related controls. Since numerous data support the possibility of rejuvenation of the brain, muscles, and other tissues using the model of heterochronic parabiosis, as well as opposite data, we planned to assess the overall effect of this long-term blood exchange on the rate of organism aging. We measured the lifespan of animals that exchanged with blood for 3 months and then were disconnected. Median and maximum life expectancy decreased in young heterochronic parabionts compared with the isochronic control. Old heterochronic parabionts showed only a small trend towards an increase in the median lifespan but it was not statistically significant, and the maximum lifespan did not change compared to the isochronic parabionts. These data support our assumption that old blood contains factors capable of inducing aging in young animals. Finding and selective suppression of aging factor production in the organism could be the key research field for life extension.

PMID:35747947 | DOI:10.1089/rej.2022.0029

Prostate. 2022 Jun 23. doi: 10.1002/pros.24402. Online ahead of print.

ABSTRACT

BACKGROUND: To investigate the prognostic value and potential therapeutic target of the baseline serum hormones in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone.

METHODS: This retrospective study was performed in patients with mCRPC receiving abiraterone acetate (AA) from July 2016 to September 2020. Patients who had serum hormone tests within 2 weeks before AA treatment were included. Univariate analysis and Cox regression were performed to evaluate the correlation of sex hormones with progression-free survival (PFS) and overall survival (OS). Prolactin (PRL) expression in the clinical specimens was evaluated by immunohistochemistry. Bone metastases were quantified by automated Bone Scan Index (aBSI).

RESULTS: The study included 61 patients with a median follow-up of 19.0 months. Patients with lower baseline PRL levels (median) responded better to AA than those with higher baseline PRL levels as indicated by prostate-specific antigen (PSA) reduction (PSA90, 66.7% vs. 25.8%, p = 0.001), PFS (19.6 vs. 7.9 months), and OS (52.8 vs. 19.2 months). Cox regression adjusted for clinical factors also confirmed that baseline PRL level was an independent predictive factor for PFS (hazard ratio = 1.096, p = 0.007). Prostatic PRL expression increased as the disease progressed. PRL expression was also detected in biopsy samples from bone metastasis but not in normal bone tissue, and the serum PRL levels were positively correlated with aBSIs (r = 0.28, p = 0.037).

CONCLUSIONS: Serum PRL levels are predictive of response to AA in patients with mCRPC. Serum PRL levels are positively correlated with the volume of metastatic bone disease.

PMID:35747943 | DOI:10.1002/pros.24402

Pediatr Obes. 2022 Jun 23:e12955. doi: 10.1111/ijpo.12955. Online ahead of print.

ABSTRACT

BACKGROUND: Cord blood leptin is an indicator of neonatal fat mass and could shape postnatal adiposity trajectories. Investigating genetic polymorphisms of the leptin receptor gene (LEPR) could help understand the mechanisms involved.

OBJECTIVES: We aimed to investigate the association of cord blood leptin level and the LEPR rs9436303 polymorphism, with body mass index (BMI) at adiposity peak (AP) and age at adiposity rebound (AR).

METHODS: In the EDEN cohort, BMI at AP and age at AR were estimated with polynomial mixed models, for 1713 and 1415 children, respectively. Multivariable linear regression models allowed for examining the associations of cord blood leptin level and LEPR rs9436303 genotype with BMI at AP and age at AR adjusted for potential confounders including birth size groups. We also tested interactions between cord blood leptin level and rs9436303 genotype.

RESULTS: Increased leptin level was associated with reduced BMI at AP and early age at AR (comparing the highest quintile of leptin level to the others). Rs9436303 G-allele carriage was associated with increased BMI at AP and later age at AR but did not modulate the association with leptin level.

CONCLUSION: These results illustrate the role of early life body composition and the intrauterine environment in the programming of adiposity in childhood.

PMID:35747935 | DOI:10.1111/ijpo.12955

Zhongguo Fei Ai Za Zhi. 2022 Jun 20;25(6):409-419. doi: 10.3779/j.issn.1009-3419.2022.102.17.

ABSTRACT

BACKGROUND: The incidence of symptomatic radiation pneumonitis (RP) and its relationship with dose-volume histogram (DVH) parameters in non-small cell lung cancer (NSCLC) patients receiving epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and concurrent once-daily thoracic radiotherapy (TRT) remain unclear. We aim to analyze the values of clinical factors and dose-volume histogram (DVH) parameters to predict the risk for symptomatic RP in these patients.

METHODS: Between 2011 and 2019, we retrospectively analyzed and identified 85 patients who had received EGFR-TKIs and once-daily TRT simultaneously (EGFR-TKIs group) and 129 patients who had received concurrent chemoradiotherapy (CCRT group). The symptomatic RP was recorded according to the Common Terminology Criteria for Adverse Event (CTCAE) criteria (grade 2 or above). Statistical analyses were performed using SPSS 26.0.

RESULTS: In total, the incidences of symptomatic (grade≥2) and severe RP (grade≥3) were 43.5% (37/85) and 16.5% (14/85) in EGFR-TKIs group vs 27.1% (35/129) and 10.1% (13/129) in CCRT group respectively. After 1:1 ratio between EGFR-TKIs group and CCRT group was matched by propensity score matching, chi-square test suggested that the incidence of symptomatic RP in the MATCHED EGFR-TKIs group was higher than that in the matched CCRT group (χ2=4.469, P=0.035). In EGFR-TKIs group, univariate and multivariate analyses indicated that the percentage of ipsilateral lung volume receiving ≥30 Gy (ilV30) [odds ratio (OR): 1.163, 95%CI: 1.036-1.306, P=0.011] and the percentage of total lung volume receiving ≥20 Gy (tlV20) (OR: 1.171, 95%CI: 1.031-1.330, P=0.015), with chronic obstructive pulmonary disease (COPD) or not (OR: 0.158, 95%CI: 0.041-0.600, P=0.007), were independent predictors of symptomatic RP. Compared to patients with lower ilV30/tlV20 values (ilV30 and tlV20<cut-off point values) and without COPD, patients with higher ilV30/tlV20 values (ilV30 and tlV20>cut-off point values) and COPD had a significantly higher risk for developing symptomatic RP, with a hazard ratio (HR) of 1.350 (95%CI: 1.190-1.531, P<0.001).

CONCLUSIONS: Patients receiving both EGFR-TKIs and once-daily TRT were more likely to develop symptomatic RP than patients receiving concurrent chemoradiotherapy. The ilV30, tlV20, and comorbidity of COPD may predict the risk of symptomatic RP among NSCLC patients receiving EGFR-TKIs and conventionally fractionated TRT concurrently.

PMID:35747920 | DOI:10.3779/j.issn.1009-3419.2022.102.17

J Man Manip Ther. 2022 Jun 23:1-7. doi: 10.1080/10669817.2022.2092822. Online ahead of print.

ABSTRACT

INTRODUCTION: Current evidence supports the inclusion of directional preference exercises for a subgroup of patients with low back (LBP) and leg pain. Recent pain neuroscience strategies have suggested that cortical restructuring associated with movement activating the body map representation in the brain might account for the observed improvement with the directional preference approach.

OBJECTIVES: To explore whether or not a motor imagery directional preference approach would result in any changes in patients with LBP and leg pain.

METHODS: A consecutive convenience sample of patients with LBP and leg pain were recruited at two outpatient physical therapy clinics. Measurements of LBP, leg pain, fear-avoidance beliefs (FABQ), pain catastrophizing (PCS), active lumbar flexion, and straight leg raise (SLR) were compared before and immediately after a virtual (motor imagery) directional preference exercise.

RESULTS: Statistically significant differences for LBP, FABQ, PCS, active lumbar flexion, and SLR were observed, but only SLR changes met or exceeded the minimally clinically important difference (MCID).

CONCLUSIONS: A brief virtual motor imagery extension treatment yielded some immediate positive shifts in patients presenting to physical therapy with LBP and leg pain. Our results indicate that randomized comparison trials are needed to determine the effect of this intervention on the short- and longer-term outcomes in patients with LBP and leg pain.

PMID:35739614 | DOI:10.1080/10669817.2022.2092822

Early Interv Psychiatry. 2022 Jun 23. doi: 10.1111/eip.13318. Online ahead of print.

ABSTRACT

AIM: In 2016 NICE updated its guidance, extending the age to which early intervention in psychosis (EIP) services treat patients following their first episode of psychosis, to 65 years, from the previous cut-off of 35 years. The aim of this service evaluation was to identify differences in the demographic details, diagnoses, and treatments between patients below and above 35 years to identify any unmet needs in the latter age category.

METHODS: A total of 100 patients from the caseload were randomly selected, with 50 from each age group, to analyse in further detail. Descriptive statistics was predominantly used due to the relatively small sample size.

RESULTS: The over 35 s were predominantly female (62%), whilst the under 35 s were predominantly male (66%). There was a statistically significantly higher rate of substance misuse in the under 35 s. Whilst schizophrenia was the most common diagnosis in both groups, higher rates of delusional disorders and psychosis NOS were observed in the over 35 s. In both age groups, a median of two different medications was used per patient. However, amongst the over 35 s there is less use of psychological therapy and of support, time and recovery workers (STR workers).

CONCLUSION: There are distinct differences between the two age groups including demographic and diagnostic features. Being historically youth based, EIP services needs to ensure that treatments offered are tailored to meet the need of the older age demographic who have different needs.

PMID:35739609 | DOI:10.1111/eip.13318

Infect Agent Cancer. 2022 Jun 23;17(1):35. doi: 10.1186/s13027-022-00449-9.

ABSTRACT

The mouse mammary tumour virus (MMTV) is implicated in the aetiology of murine mammary carcinomas and a variant of it, the type B leukemogenic virus, can cause murine thymic lymphomas. Interestingly, a MMTV-like virus is suspected to be involved in human breast cancer and feline mammary carcinomas. However, to date, no cases of MMTV-like sequence amplifications have been described in lymphoid neoplasms in veterinary literature. The aim of this study was to investigate the presence of env nucleotide sequences and protein 14 (p14) of a MMTV-like virus in fifty-three feline lymphoma samples. Our results show that MMTV-like sequences were detected in 5/53 tumours (9.4%): three gastrointestinal lymphomas (one B-type diffuse large, one B-type small non-cleaved, and one T-type diffuse mixed lymphoma); and two nasal lymphomas (one B-type diffuse small cleaved lymphoma and one B-type diffuse mixed lymphoma). P14 expression was detected in the cytoplasm, and rarely in nuclei, exclusively of neoplastic cells from PCR-positive tumours. The correlation between the presence of the MMTV-env like sequences (MMTVels) and p14 antigen was statistically significant in nasal lymphomas. All cats with MMTVels-positive lymphoma had a history of contact with the outdoor environment and/or catteries, and two deceased subjects shared their environment with cats that also died of lymphoma. In conclusion, this study succeeds in demonstrating the presence of MMTVels and p14 in feline lymphomas. The characterization of the immunophenotype of MMTVels-positive lymphomas could contribute to the understanding of a possible role of a MMTV-like virus in feline tumour aetiology. The significant association between the presence of the viral sequences in lymphoid tumours and their nasal localization, together with the data collected through supplementary anamnesis, should be further analysed in order to understand the epidemiology of the virus.

PMID:35739602 | DOI:10.1186/s13027-022-00449-9

Orphanet J Rare Dis. 2022 Jun 23;17(1):245. doi: 10.1186/s13023-022-02375-w.

ABSTRACT

BACKGROUND: Congenital pseudarthrosis of the tibia (CPT) is a rare disease occurring in children. The aim of this study is to identify the factors affecting bone union and re-fracture after surgery for CPT and to provide reliable evidence for clinics.

METHODS: We collected the detailed information of 255 cases with Crawford IV CPT treated by combined surgery in our hospital from 2013 to 2020. Basic characteristics were recorded. Univariate variance and logistic regression analysis were used to compare the correlations between factors and outcomes.

RESULTS: 92.5% of patients achieved primary union, 7.5% of patients had non-union and 13.3% of patients had re-fracture. Logistic regression analysis showed that age at index surgery (Coef. = 0.171, 95%CI 0.015-0.327, P = 0.032), and CPT location (Coef. = – 1.337, 95%CI – 2.218-0.456, P = 0.003) had statistical differences, while no factors had significant correlation with re-fracture. Furthermore, ROC curve showed that the optimal age threshold for first surgery was 2.37 years old.

CONCLUSIONS: For patients with Crawford IV CPT treated by combined surgery, the younger the age at index surgery and the closer the CPT location to the distal end, the easier to achieve bone union.

PMID:35739599 | DOI:10.1186/s13023-022-02375-w