Characteristics and immune checkpoint inhibitor effects on non-smoking non-small cell lung cancer with KRAS mutation: A single center cohort (STROBE-compliant)

Kirsten rat sarcoma (KRAS) mutation (KRASm) is associated with poor prognosis in non-small cell lung cancer (NSCLC) patients. We have aimed to survey NSCLC patients harboring KRASm in Taiwan, where never-smoking lung adenocarcinoma predominates, and analyze the immune checkpoint inhibitor effect on NSCLC harboring KRASm.NSCLC patients with KRASm were enrolled and tested on programmed death-ligand 1 (PD-L1) expression using available tissue. We analyzed their clinical features, PD-L1 status, responses to ICIs, and overall survival (OS).We studied 93 patients with a median age 66.0 years, 23.7% of whom were women, and 22.6% were never-smokers. The results showed that G12C (36.6%) was the most common KRASm. In 47 patients with available tissue for PD-L1 testing, PD-L1 expression was positive in 66.0% of patients, while PD-L1 ≥50% was higher in ever-smokers (P = .038). Among 23 patients receiving ICI treatment, those with PD-L1 ≥50% experience a 45.5% response rate to ICI. There were benefits from ICI treatment on OS compared with no ICI treatment (median OS 35.6 vs 9.8 months, P = .002) for all of our patients, and for patients with PD-L1 ≥50% (median OS not-reached vs 8.4 months, P = .008). There were no differences in survival across different KRAS subtypes (P = .666).Never-smokers composed more than one-fifth of KRASm in NSCLC in Taiwan. A high PD-L1 expression was related to smoking history and responded well to ICI. ICI treatment improved the OS in NSCLC patients with KRASm, particularly those with PD-L1 ≥50%.     

Correction: Discovery of 8-prenylnaringenin from hop (Humulus lupulus L.) as a potent monoacylglycerol lipase inhibitor for treatments of neuroinflammation and Alzheimer’s disease

Correction for ‘Discovery of 8-prenylnaringenin from hop (Humulus lupulus L.) as a potent monoacylglycerol lipase inhibitor for treatments of neuroinflammation and Alzheimer’s disease’ by Min-Che Tung et al., RSC Adv., 2021, 11, 31062–31072, https://doi.org/10.1039/D1RA05311F.

The authors regret that the name of one of the authors (Hsing-Mien Hsu) was shown incorrectly in the original article. The corrected author list is as shown above.The authors also regret an incorrect version of Fig. 7 was included in the original article. The correct version of Fig. 7 is presented below.Open in a separate windowFig. 7The dose-dependent inhibitions of the identified inhibitors against hMAGL.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers.     

Exposure to PM2.5 causes genetic changes in fetal rat cerebral cortex and hippocampus

PM_2.5 travels along the respiratory tract and enters systemic blood circulation. Studies have shown that PM_2.5 increases the incidence of various diseases not only in adults but also in newborn infants. It causes chronic inflammation in pregnant women and retards fetal development. In this study, pregnant rats were exposed to PM_2.5 for extended periods of time and it was found that PM_2.5 exposure increased immune cells in mother rats. In addition, cytokines and free radicals rapidly accumulated in the amniotic fluid and indirectly affected the fetuses. The authors collected cerebral cortex and hippocampus samples at E18 and analyzed changes of miRNA levels. Expression levels of cortical miR‐6315, miR‐3588, and miR‐466b‐5p were upregulated, and positively correlated with the genes Pkn2 (astrocyte migration), Gorab (neuritogenesis), and Mobp (allergic encephalomyelitis). In contrast, PM_2.5 decreased expression of miR‐338‐5p and let‐7e‐5p, both related to mental development. Further, PM_2.5 exposure increased miR‐3560 and let‐7b‐5p in the hippocampus, two proteins that regulate genes Oxct1 and Lin28b that control ketogenesis and glycosylation, and neural cell differentiation, respectively. miR‐99b‐5p, miR‐92b‐5p, and miR‐99a‐5p were decreased, leading to reduced expression of Kbtbd8 and Adam11 which reduced cell mitosis, migration, and differentiation, and inhibited learning abilities and motor coordination of the fetus. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1412–1425, 2017.     

Comparison of chemical compositions and osteoprotective effects of different sections of velvet antler

Ethnopharmacological relevance

Velvet antlers (VA) have been claimed for centuries to have numerous medical benefits including strengthen bones. To investigate and compare the anti-osteoporotic activities from different sections of VA.

Materials and methods

Fresh VA prepared from farmed sika deers (Cervus nippon) was divided into upper (VAU), middle (VAM), and basal (VAB) sections. The chemical constituents and anti-osteoporotic effect of different sections from VA were evaluated using ovariectomized rats.

Results

Levels of water-soluble extracts, diluted alcoholic extract, amino acids, testosterone, insulin-like growth factor (IGF)-1and testosterone plus estradiol significantly differed among the different sections. Levels of these constituents were significantly higher in the upper section than in the basal section. Moreover, levels of testosterone and IGF-1 of the VAM were also significantly higher than those of the VAB. Calcium level increased downward from the tip with statistical significance. The strength of vertebrae increased in all VA-treated groups compared to the control, but only treatment with VAU and VAM increased the strength of the femur and the microarchitecure of the trabecular bone. Alkaline phosphatase levels of VAU- and VAM-treated groups significantly decreased, but osteocalcin did not significantly change. Moreover, VAU and VAM dose-dependently increased proliferation and mineralization of MC3T3-E1 cells.

Conclusion

Our study provides strong evidence for the regional differences in the effectiveness of velvet antler in treating osteoporosis. However, further studies are needed to elucidate the bioactive chemical constituents associated with the anti-osteoporotic effects of velvet antler.     

A comparison of different severities of nausea and vomiting during pregnancy relative to stress, social support, and maternal adaptation

A cross-sectional and comparative research design with convenience sampling was used to recruit pregnant women from prenatal clinics in southern Taiwan between 2002 and 2003 to examine the differences in perceived stress, social support, and maternal psychosocial adaptation among women with different severities (mild or less than mild, moderate, and severe) of nausea and vomiting during pregnancy. A total of 150 pregnant women participated in this study. One-way analysis of variance indicated that perceived stress was significantly different among the 3 groups. The least significant difference post-hoc test revealed that pregnant women with mild nausea and vomiting had significantly lower stress than did pregnant women with severe nausea and vomiting. The severity of nausea and vomiting was significantly associated with the Prenatal Self Evaluation Questionnaire subscales for "acceptance of pregnancy" and "fear of helplessness and loss of control in labor." Social support and maternal psychosocial adaptation were not significantly different among these three groups. The degree of perceived stress and maternal psychosocial adaptation may be related to the severity of nausea and vomiting during pregnancy.     

Success of targeted transperineal biopsy in patients on surveillance for grade group 1 prostate cancer

IntroductionWe aimed to determine the minimum cross-sectional ellipsoid area on magnetic resonance (MR) of intraprostatic nodules that best predicts for subsequent targeted biopsies revealing ≥ grade group (GG) 2 disease.MethodsForty-six patients previously diagnosed with GG 1 prostate adenocarcinoma who received cognitively fused, MR-guided, transperineal targeted biopsies in addition to six random biopsies were included in this analysis. A Youden cutpoint analysis was used to determine the ellipsoid area in the axial plane best predicting for ≥GG 2 disease within the targeted biopsy cores and logistic regression used to assess the result.ResultsMedian time from MR imaging to targeted biopsy was 2.4 (1.4–5.5) months. Forty of 46 (87%) patients had one nodule and 6/46 (13%) had two separate nodules on MR that received targeted biopsy. Of the 52 nodules, five (10%), 33 (63%), and 14 (27%) were Prostate Imaging-Reporting and Data System (PI-RADS) 3, 4, and 5, respectively. Thirteen (25%), six (12%), and 33 (64%) were in the anterior, medial, and posterior regions of the prostate, respectively. Median area was 0.72 (0.49–1.29) cm² (average diameter 9.5 mm). Fifteen of 46 (33%) patients had ≥1 random biopsy and 20/52 (38%) nodules had ≥1 targeted biopsy revealing ≥GG 2 disease. The optimal area cutpoint was ≥0.7 cm², with an area under the curve of 0.671 (0.510–0.832). On logistic regression, area ≥0.7 cm² was solely predictive of targeted biopsy revealing ≥GG 2 disease (odds ratio 6.5, 1.3–32.4, p=0.022).ConclusionsNodule area ≥0.7 cm² may predict for transperineal-based targeted biopsies being positive for ≥GG 2 disease when 1–2 cores are taken.     

Adult‐onset inflammatory linear verrucous epidermal nevus: Immunohistochemical studies and review of the literature

Adult‐onset inflammatory linear verrucous epidermal nevus (ILVEN) is an uncommon cutaneous disease compared to childhood‐onset ILVEN. The typical histopathologic features are alternating parakeratosis and orthokeratosis with an absent granular layer underneath parakeratosis, in contrast to a thickened granular layer below the foci of orthokeratosis in psoriasiform epidermal hyperplasia. Herein, we present a 49‐year‐old woman with typical clinical and histopathologic characteristics of adult‐onset ILVEN, including linear arrangement of thick scaly papules and plaques localized on the medial side of her right leg, ankle, and foot. Immunohistochemical studies included involucrin, Ki‐67, and keratin‐10. Compared to the staining pattern in psoriasis, the expression of involucrin in this case was of lower intensity and localized to upper epidermal layers with relatively less extensive staining beneath regions of parakeratosis as compared to orthokeratosis; Ki‐67 showed lower basal layer proliferative activity; and keratin‐10 showed a greater intensity of staining within suprabasal epidermis.     

Insulin Use and Smoking Jointly Increase the Risk of Bladder Cancer Mortality in Patients With Type 2 Diabetes

BackgroundWhether insulin use predicts bladder cancer mortality has not been investigated. Furthermore, it is not known whether insulin use and smoking jointly influence the risk.Materials and MethodsA total of 86,939 patients (40,014 men, 46,925 women) with type 2 diabetes mellitus (T2DM) and aged ≥ 25 years in a nationally representative cohort were followed prospectively from 1995 to 2006 for bladder cancer mortality. Cox regression was used considering the following independent variables: age, sex, diabetes duration, body mass index, smoking, insulin use, and area of residence. The models were created for patients aged ≥ 25 and ≥ 65 years, separately; and sensitivity analyses were conducted after excluding (1) patients with duration between onset of diabetes and bladder cancer mortality < 5 years, and (2) patients with diabetes duration at recruitment < 3 years. The joint effect of insulin use and smoking was evaluated.ResultsPatients who died of bladder cancer were characterized by older age, male predominance, longer diabetes duration, smoking, and insulin use. In multivariable Cox models, age, male sex, and insulin use were consistently predictive for bladder cancer mortality in all analyses, whereas the other variables were not. The adjusted hazard ratios for bladder cancer mortality for insulin users vs. nonusers ranged from 1.877 to 2.502 in different models (all P values < .05). Insulin use and smoking jointly increased the adjusted hazard ratio to 3.120 (95% confidence interval, 1.329-7.322).ConclusionsInsulin use is significantly predictive for bladder cancer mortality in patients with T2DM. Insulin use and smoking jointly increase the risk.     

Dopamine Modulation of GABAergic Function Enables Network Stability and Input Selectivity for Sustaining Working Memory in a Computational Model of the Prefrontal Cortex

Dopamine modulation of GABAergic transmission in the prefrontal cortex (PFC) is thought to be critical for sustaining cognitive processes such as working memory and decision-making. Here, we developed a neurocomputational model of the PFC that includes physiological features of the facilitatory action of dopamine on fast-spiking interneurons to assess how a GABAergic dysregulation impacts on the prefrontal network stability and working memory. We found that a particular non-linear relationship between dopamine transmission and GABA function is required to enable input selectivity in the PFC for the formation and retention of working memory. Either degradation of the dopamine signal or the GABAergic function is sufficient to elicit hyperexcitability in pyramidal neurons and working memory impairments. The simulations also revealed an inverted U-shape relationship between working memory and dopamine, a function that is maintained even at high levels of GABA degradation. In fact, the working memory deficits resulting from reduced GABAergic transmission can be rescued by increasing dopamine tone and vice versa. We also examined the role of this dopamine–GABA interaction for the termination of working memory and found that the extent of GABAergic excitation needed to reset the PFC network begins to occur when the activity of fast-spiking interneurons surpasses 40 Hz. Together, these results indicate that the capability of the PFC to sustain working memory and network stability depends on a robust interplay of compensatory mechanisms between dopamine tone and the activity of local GABAergic interneurons.