Clinical Experience of External Application of Clearing Heat and Removing Dampness in Relieving Grade 2 to 3 Rash Caused by Programed Cell Death Protein 1 (PD-1)/Programed Cell Death Ligand 1 (PD-L1) Inhibitors: A Single-Center Retrospective Study.

OBJECTIVE: In China, grade 2 to 3 immune-related rash will probably lead to the interruption of immunotherapy. Corticosteroid (CS) is the main treatment, but not always effective. The external application of clearing heat and removing dampness, which is represented by Qing-Re-Li-Shi Formula (QRLSF), has been used in our hospital to treat immune-related cutaneous adverse events (ircAEs) for the last 5 years. The purpose of this study was to discuss its efficacy and safety in the treatment of grade 2 to 3 rash. METHODS: A retrospective study of patients with grade 2 to 3 immune-related rash in our hospital from December 2019 to December 2022 was conducted. These patients received QRLSF treatment. Clinical characteristics, treatment outcome, and health-related quality of life (HrQoL) were analyzed. RESULTS: Thirty patients with grade 2 to 3 rash (median onset time: 64.5 days) were included. The skin lesions of 24 cases (80%) returned to grade 1 with a median time of 8 days. The accompanying symptoms were also improved with median time of 3 to 4 days. The addition of antihistamine (AH) drug didn't increase the efficacy of QRLSF (AH + QRLSF: 75.00% vs QRLSF: 83.33%, P = .66). No significant difference was observed in the efficacy of QRLSF treatment regardless of whether patients had previously received CS therapy (untreated population: 88.24% vs treated population: 69.23%, P = .36). During 1-month follow-up, 2 cases (8.33%) underwent relapses. In terms of HrQoL, QRLSF treatment could significantly reduce the median scores of all domains of Skindex-16, including symptoms (39.58 vs 8.33, P < .0001), emotions (58.33 vs 15.48, P < .0001), functioning (46.67 vs 13.33, P < .0001) and composite (52.60 vs 14.06, P < .0001). CONCLUSION: External application of clearing heat and removing dampness was proven to be an effective and safe treatment for such patients. In the future, high-quality trials are required to determine its clinical application in the field of ircAEs.

Oenothein B ameliorates hepatic injury in alcoholic liver disease mice by improving oxidative stress and inflammation and modulating the gut microbiota.

Introduction: Alcoholic liver disease (ALD) is a global health problem for which there is no current food and drug administration (FDA)-approved therapy. Oenothein B (OEB) is a macrocyclic dimer ellagic tannin that possesses abundant biological activities including antioxidant, anti-inflammation, antitumor, immunomodulatory, and antimicrobial properties. Materials and methods: In this study, the hepatoprotective effect of OEB against ALD was investigated in vivo and in vitro. Results: We found that OEB treatment dramatically reduced alcohol-induced hepatic injury, as evidenced by decreased levels of aminotransferases and inflammatory biomarkers and increased antioxidant capacity in OEB-treated groups. Discussion: OEB treatment alleviated oxidative stress by upregulating the Keap1/Nrf2 signaling pathway and inhibited inflammation by downregulating the TLR4/NF-κB signaling pathway. Additionally, OEB treatment positively improved alcohol-induced intestinal microbial dysbiosis by modulating the structure and composition of gut microbiota. Interestingly, we observed the increasement of short-chain fatty acid (SCFA) producers (Muribaculaceae) and the decreasement of Gram-negative bacteria (Akkermansia) in the OEB treatment groups, which may contribute to the inhibition of hepatic oxidative stress and inflammation via the gut-liver axis. In summary, our findings indicate that OEB is a promising therapeutic strategy for preventing and treating ALD.

Stevens-Johnson syndrome/toxic epidermal necrolysis successfully treated with Chinese herbal medicine Pi-Yan-Ning: A case report.

Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is a rare adverse cutaneous reaction with a low incidence and high mortality. Despite posing a serious threat to patients' health and lives, there is no high-quality evidence for a standard treatment regimen. Here we report the case of a 62-year-old man with stage IV pancreatic cancer who experienced immunotherapy-induced SJS/TEN. After consensus-based regular treatments at a local hospital, his symptoms became worse. Thus, he consented to receive Chinese herbal medicine (CHM) therapy. The affected parts of the patient were treated with the CHM Pi-Yan-Ning which was applied externally for 20 min twice a day. After 7 days of treatment, the dead skin began peeling away from the former lesions that had covered his hands, feet, and lips, indicating that skin had regenerated. After 12 days of treatment, the patient's skin was completely recovered. In this case, SJS/TEN was successfully treated with Pi-Yan-Ning, suggesting that there might be tremendous potential for the use of Pi-Yan-Ning in the treatment of severe skin reactions to drug treatments. Further basic investigations and clinical trials to explore the mechanism and efficacy are needed.

Yang-Yin-Jie-Du decoction overcomes gefitinib resistance in non-small cell lung cancer via down-regulation of the PI3K/Akt signalling pathway.

CONTEXT: Yang-Yin-Jie-Du Decoction (YYJDD) was used to improve gefitinib efficacy in our clinical practice, but its mechanism remains unclear. OBJECTIVE: This study explored if YYJDD could reverse gefitinib resistance. MATERIALS AND METHODS: H1975 cells were exposed to control, 10 µM gefitinib, 3.2 mg/mL YYJDD or combination treatment. Cell viability was detected by MTT during 0-96 h. Apoptosis and the PI3K/Akt proteins were tested by flow cytometry and western-blot at 24 h. LY294002 was applied to further determine the role of the PI3K/Akt. 23 BALB/c nude xenograft mice received normal saline (n = 5), 80 mg/kg gefitinib (n = 6), 2.35 g/kg lyophilised powder of YYJDD (n = 6) or combination treatment (n = 6) by gavage for 4 weeks and submitted to TUNEL, immunohistochemistry, and western-blot. RESULTS: In vitro, gefitinib (IC50: 20.68 ± 2.06 µM) and YYJDD (IC50: 6.6 ± 0.21 mg/mL) acted in a moderate synergistic way. Combination treatment inhibited cell viability from 100% to 25.66%. Compared to gefitinb (33.23 ± 3.99%), cell apoptosis was increased with combination treatment (54.11 ± 7.32%), accompanied by down-regulation of the PI3K/Akt. LY294002 further inhibited cell viability, increased apoptosis, and down-regulated p-Akt/Akt. In vivo, the tumour sizes in the combination group (1165.13 ± 157.79 mm3) were smaller than gefitinib alone (1630.66 ± 208.30 mm3). The positive rate of TUNEL staining was increased by combination treatment (22.33 ± 2.75%) versus gefitinib (7.37 ± 0.87%), while the PI3K/Akt was down-regulated. DISCUSSION AND CONCLUSION: YYJDD has potential to overcome gefitinib resistance. Future investigations should be focussed on its specific targets.

Neoadjuvant therapy of cetuximab combined with chemoradiotherapy in rectal cancer: A single-arm meta-analysis of noncomparative clinical studies and randomized controlled trials.

OBJECTIVE: Preoperative chemoradiotherapy combined with radical resection has reduced local recurrence rates in rectal cancer. Cetuximab shows improvement in rectal cancer treatment. But the role for neoadjuvant therapy of cetuximab combined with chenmoradiotherapy in rectal cancer remains unclear. The present study aimed to use meta-analytical techniques to assess its benefit and risk. MATERIALS AND METHODS: We searched PubMed, the Cochrane Library, Embase to identify the correlational non-comparative clinical studies and randomized controlled trials (RCTs). The primary endpoints of interest were pathological complete response (pCR), complete response (CR), partial response (PR), stable disease, progressive disease (PD), R0-resection, R1-resection, and R2-resection. The secondary included any grade of toxicity. RESULTS: Eleven investigations (9 noncomparative open-label cohort studies and 2 randomized controlled trials) involving 550 patients were ultimately included. The pooled estimates of pCR was 10% (95% confidence interval [CI]: 7%-13%, I2 = 55.9%). Simultaneously, only a small amount of patients achieved CR (11%, 95% CI: 7%-15%, I2 = 44.0%), which was consistent with pCR. Besides, R0 resection (93%, 95% CI: 90%-96%, I2 = 16.5%) seemed to be increased but need further exploration. The safety was also calculated, and most of the toxicities were moderate. CONCLUSION: Neoadjuvant therapy of cetuximab combined with chemoradiotherapy could not improve pCR. The raise of R0-resection rate needed to be verified by more high-quality and well-designed RCTs. Meanwhile, the morbidity of toxicity was relatively mild and acceptable.

The effects of O-GlcNAc alteration on Alzheimer-like neurodegeneration in SK-N-SH cells.

BACKGROUND: O-GlcNAcylation is a highly dynamic post-translational modification that plays a key role in regulating phosphorylation of protein and cell survival. The proteins O-GlcNAcylation level is regulated dynamically by O-GlcNAc transferase (OGT) and ß-N-acetylglucosaminidase (O-GlcNAcase, OGA). Although previous studies have suggested the role of O-GlcNAcylation in neurodegenerative diseases, the mechanism of O-GlcNAcylation in Alzheimer's disease (AD) remains unclear. METHODS: The decrease of O-GlcNAcylation by alloxan, an OGT inhibitor, and increase by NAG-thiazolines (NAG-Ae), an O-GlcNAcase inhibitor were tested to investigate the effects of O-GlcNAc alteration on AD like neurodegeneration in SK-N-SH cells. RESULTS: The level of O-GlcNAcylation was decreased in alloxan treated cells and increased in NAG-Ae treated cells. Meanwhile, it was observed that both abnormal phosphorylation of NFs in cell bodies and apoptosis induced by alloxan treatment can be resisted by pretreatment or simultaneous treatment with appropriate NAG-Ae. CONCLUSION: These results demonstrated that increasing O-GlcNAc with NAG-Ae protected AD like neurodegeneration from NFs hyperphosphorylation and the cell loss, suggesting the role of O-GlcNAc in the pathogenesis and therapy of AD.

Simple approach for ultrasensitive electrochemical immunoassay of Clostridium difficile toxin B detection.

Clostridium difficile toxin B (Tcd B), as one of the primary contributing factors to the pathogenesis of C. difficile-associated diseases, has raised serious public concerns due to its virulence, spore-forming ability and persistence with major types of infectious diarrhea diseases, and been used as a potential biomarker in clinical diagnoses. Thus, a simple method for the determination of Tcd B was developed based on a sandwich-type electrochemical immunosensor. Greatly enhanced sensitivity was achieved based on fabricating the immunosensor by layer-by-layer coating carbon nanotubes (MWCNTs), Prussian blue (PB), Chitosan (CS), Glutaraldehyde (GA) composite on the working electrode as well as using graphene oxide (GO) as a nanocarrier in a multienzyme amplification strategy. In comparison with conventional methods, the proposed immunoassay exhibited high sensitivity and selectivity for the detection of Tcd B, providing a better linear response range from 0.003 to 320 ng/mL and a lower limit of detection (LOD) of 0.7 pg/mL (S/N=3) under optimal experimental conditions. The immunosensor exhibited convenience, low cost, rapidity, good specificity, acceptable stability and reproducibility. Moreover, satisfactory results were obtained for the determination of Tcd B in real human stool samples, indicating that the developed immunoassay has the potential to find application in clinical detection of Tcd B and other tumor markers as an alternative approach.

Relationship between acute stroke outcome, aspirin resistance, and humoral factors.

BACKGROUND: The relationship between biochemical aspirin resistance (AR) and functional outcome of acute ischemic stroke is uncertain. METHODS: Prospectively, 269 patients with acute ischemic stroke were recruited. Their responsiveness to aspirin was evaluated by platelet function analyzer (PFA-100). All patients received blood tests for fibrinogen, high-sensitivity C-reactive protein (hs-CRP), CD40-ligand, P-selectin, intercellular adhesion molecule -1, von Willebrand factor (vWF), and D-dimer. The patients' National Institutes of Health Stroke Scale and modified Rankin Scale scores were recorded on admission, at 30 days, and at 90 days after stroke. RESULTS: Closure-time measured by PFA-100 equipped with epinephrine/collagen cartridge (Epi-CT) was <193 seconds (defined as AR) in 83 patients (30.9%). Patients with AR were less likely to have favorable outcome at 30 days (47.0%, p = 0.047; odds ratio: 0.69, 0.48-0.99) and 90 days (57.8%, p = 0.037; odds ratio: 0.69, 0.47-0.97) after stroke compared with those of patients without AR (60.2% and 71.0%, respectively). The Epi-CT correlated with closure-time measured by adenosine diphosphate/collagen cartridge (r = 0.241, p < 0.001), blood white cell count (r = -0.125, p = 0.041), low density lipoprotein cholesterol (r = 0.120, p = 0.050), hs-CRP (r = -0.150, p = 0.015), vWF (r = -0.134, p = 0.028), and body mass index (r = 0.143, p = 0.019). Multivariate logistic regression analysis showed that higher National Institutes of Health Stroke Scale at admission, atrial fibrillation, increased plasma levels of hs-CRP, and D-dimer were independent predictors for unfavorable stroke outcome at 90 days. CONCLUSION: Aspirin resistance evaluated by PFA-100 test was associated with unfavorable 90-day outcome. However, AR determined by PFA-100 dose not predict 90-day functional outcome. The results of PFA-100 testing represented a complex interaction between drug effect, inflammatory reaction, and prothrombotic activity.

Prevalence and associated factors of sexual dysfunction in cervical cancer patients.

INTRODUCTION: Cervical cancer (CC), compared with other gynecological cancers, has critical implications for women's sexual lives. For most Asian people, the issue of sexual dysfunction (SD) is treated as a taboo especially in a conservative culture. As a result, little is known about the prevalence of SD among CC patients. AIMS: The purpose of this study was to investigate the prevalence of SD and associated factors among CC patients. METHODS: We used a cross-sectional correlation design with the purposive sampling to recruit 105 CC patients from a hospital in Northern Taiwan. A structured questionnaire was used in this study to collect demographic data, disease characteristics, and information provided by the Chinese version of the Female Sexual Function Index scale. Data were analyzed by descriptive statistics, independent t-test, chi-square test, and multiple logistic regression. MAIN OUTCOME MEASURE: The prevalence of SD and the main predictors for SD were determined. RESULTS: The crude prevalence and age-standardized prevalence of SD were 66.67% and 55%, respectively. CC patients with a lower level of education (≤9th grade) (adjusted odds ratio [AOR]: 3.14; 95% confidence interval [CI]: 1.51-10.37), who were older (AOR: 1.16; 95% CI: 1.07-1.25), who had received no sexual-counseling services prior to therapy or later (AOR: 4.98; 95% CI: 2.31-9.71), or were stage II or above (AOR: 4.34; 95% CI: 1.65-19.09) showed a significantly higher risk of SD compared with those without these conditions. CONCLUSIONS: Our findings are beneficial to health-care providers by identifying the prevalence of SD and by pinpointing those groups with a higher predisposition of having SD, which will allow the provision of appropriate rehabilitation.

[Factors related to sexual dysfunction in patients with cervical cancer].

BACKGROUND: Cervical cancer impacts upon the sex lives of its victims in ways that are more profound than other gynecological cancers. However, no research on sexual dysfunction issues in cervical cancer patients has previously been conducted in Taiwan. PURPOSE: The purposes of this study were to explore sexual dysfunction and related factors in patients diagnosed with cervical cancer. METHODS: The study used a cross-sectional correlation design with a convenience sampling method to recruit 105 patients from a medical center in Northern Taiwan. The structured questionnaire used in this study gathered data on respondent demographics and disease characteristics, and included a Chinese version of the Female Sexual Function Index (FSFI) scale. RESULTS: Respondents noted significant levels of pain triggered by cervical cancer. Lower level of education (below the 9th grade), increased age, lack of religious affiliation and absence of counseling prior to or during therapy were associated with significantly lower sexual dysfunction scores. These factors accounted for 54.60% of variance in sexual dysfunction. CONCLUSION: Our findings should assist healthcare providers to better understand sexual dysfunction in cervical cancer patients, detect those with higher predispositions toward such, and prescribe appropriate rehabilitation therapies to improve sexual enjoyment.

Serum interleukin-6 levels, not genotype, correlate with coronary plaque complexity.

An increased serum interleukin-6 (IL-6) level is associated with an increased risk of cardiovascular events in healthy subjects. However, it is unknown whether the level of serum IL-6 or genetic IL-6 polymorphism is correlated with the complexity of coronary plaque in patients with stable coronary artery disease (CAD). Patients with stable CAD (n = 135) were divided into 3 groups: insignificant coronary plaque (n = 77), simple coronary plaque (n = 15), and complex coronary plaque (n = 43). IL-6-174G > C polymorphism and serum levels of IL-6 and C-reactive protein (CRP) were investigated. No significant difference in the distribution of IL-6 genotypes was found among the groups. The presence of complex coronary plaque was associated with higher serum concentrations of IL-6 (P = 0.026) and CRP (P < 0.0001). To predict the presence of complex lesions, IL-6 > 5.8 ng/L and CRP > 2.6 mg/L had sensitivities of 86% and 74%, and specificities of 61% and 62%, respectively. By multivariate analysis, IL-6 > 5.8 ng/L and CRP > 2.6 mg/L were independently related to the presence of complex coronary plaque (P = 0.0002 and 0.004, respectively). IL-6 > 5.8 ng/L and CRP > 2.6 mg/L were associated with a 4.5-fold increase in the odds of having complex coronary plaque (P < 0.005). A simple measurement of the serum IL-6 level in patients with CAD can potentially identify subjects with complex coronary lesions and provide the option of aggressive medical strategies in a clinical setting.

Direct interaction of focal adhesion kinase (FAK) with Met is required for FAK to promote hepatocyte growth factor-induced cell invasion.

Focal adhesion kinase (FAK) has been implicated to be a point of convergence of integrin and growth factor signaling pathways. Here we report that FAK directly interacts with the hepatocyte growth factor receptor c-Met. Phosphorylation of c-Met at Tyr-1349 and, to a lesser extent, Tyr-1356 is required for its interaction with the band 4.1 and ezrin/radixin/moesin homology domain (FERM domain) of FAK. The F2 subdomain of the FAK FERM domain alone is sufficient for Met binding, in which a patch of basic residues (216KAKTLRK222) are critical for the interaction. Met-FAK interaction leads to FAK activation and subsequent contribution to hepatocyte growth factor-induced cell motility and cell invasion. Our results provide evidence that constitutive Met-FAK interaction may be a critical determinant for tumor cells to acquire invasive potential.

Blockade of v-Src-stimulated tumor formation by the Src homology 3 domain of Crk-associated substrate (Cas).

Crk-associated substrate (Cas) is highly phosphorylated by v-Src and plays a critical role in v-Src-induced cell transformation. In this study, we found that the Src homology (SH) 3 domain of Cas blocked v-Src-stimulated anchorage-independent cell growth, Matrigel invasion, and tumor growth in nude mice. Biochemical analysis revealed that the Cas SH3 domain selectively inhibited v-Src-stimulated activations of AKT and JNK, but not ERK and STAT3. Attenuation of the AKT pathway by the Cas SH3 domain rendered v-Src-transformed cells susceptible to apoptosis. Inhibition of the JNK pathway by the Cas SH3 domain led to suppression of v-Src-stimulated invasion. Taken together, our results indicate that the Cas SH3 domain has an anti-tumor function, which severely impairs the transforming potential of v-Src.

No association between polymorphisms of the DNA repair geneXRCC1 and cervical neoplasm risk.

OBJECTIVES: To investigate the association between genetic polymorphisms ofX-ray repair crosscomplementing group 1 (XRCC1) codons 194, 280, and 399 and cervical neoplasm susceptibility. METHODS: A community-based nested case-control study was conducted. The study population consisted of women living in Chiayi City, located in southwestern Taiwan, who had received pap smear screening between October, 1999, and December, 2000 (n=32,466). The potential cases were women having lesions greater than cervical intraepithelium neoplasm II (C1N2) reconfirmed by cervical biopsy. The potential controls (case: control=1∶2) were age matched (±2 yrs) and residency matched women who had had normal pap smears. In total, 100 cases (39 C1N2, 12 C1N3, 46 carcinoma in situ (CIS), and 3 invasive cancer) and 196 controls had the information on both questionnaire and data ofXRCC1 polymorphisms. RESULTS: The frequency ofArg/Arg, Arg/Gln, andGln/Gln in codon 399 among cases and controls was 54% (54/100), 38% (38/100), and 8% (8/100) and 58% (114/196), 37% (73/196), and 5% (9/196), respectively, which were not significantly different. No associations were also observed betweenXRCC1 codon 194 and 280 genotypes and cervical neoplasm. While dichotomized by age (<40 vs. ≥40 yrs), smoking status (active and passive smokers vs. non-smokers), and disease status (C1N2 and C1N3 vs. CIS and invasive cancer), the results remained insignificant. CONCLUSIONS: The present findings suggest thatXRRC1 codon 194, 280 and 399 genotypes may not influence cervical neoplasm risk in the Taiwanese population.

15-Deoxy-delta12,14-prostaglandin J2 induces apoptosis of a thyroid papillary cancer cell line (CG3 cells) through increasing intracellular iron and oxidative stress.

Treatment of carcinoma cell lines with 15-deoxy-delta12,14-prostaglandin J2 (15d-PGJ2), a natural ligand of the peroxisome proliferator-activated receptor-gamma, has been reported to induce apoptosis and/or inhibit proliferation. In this study, we investigated the cytotoxic effect and the action mechanisms of 15d-PGJ2 in a thyroid papillary cancer cell line, CG3. The results indicate that 15d-PGJ2 caused cytotoxicity and increased the amount of intracellular reactive oxygen species (ROS) in these cells. Mitochondrial oxidative phosphorylation inhibitors (carbonyl cyanide m-chloro-phenylhydrazone, oligomycin, cyclosporin A and rotenone), NADPH oxidase inhibitor (diphenyleneiodonium), xanthine oxidase inhibitor (allopurinol) and NO synthase inhibitor (N-monomethyl-L-arginine acetate) did not reduce the generation of ROS. However, catalase, N-acetyl-cysteine and the iron chelator desferri-oxamine decreased the intracellular ROS of 15d-PGJ2-treated CG3 cells. Furthermore, 15d-PGJ2 enhanced the accumulation of iron in the CG3 cells. These data suggest that 15d-PGJ2 induces the generation of ROS by enhancing the accumulation of intracellular iron and that the increased oxidative stress may cause apoptosis of CG3 cells.