Exploring the Immune Landscape of Cirrhosis through Weighted Gene Co-expression Network Analysis.

Cirrhosis is a persistent hepatic ailment that emerges from a range of causes, including viral infections, alcoholic liver disease, and non-alcoholic fatty liver disease. It is distinguished by the replacement of normal liver parenchyma with fibrous scar tissue, culminating in the development of hepatic insufficiency, portal hypertension, and eventual liver collapse. Several molecular and cellular mechanisms contribute to cirrhosis' pathogenesis, including activation of immune cells and dysregulation of immune-related pathways. Weighted Gene Co-expression Network Analysis (WGCNA) is a powerful data mining application used to identify gene modules and hub genes that are closely associated with specific phenotypes or conditions of interest. In this study, we performed WGCNA on publicly available gene expression datasets and subsequently assessed the roles of immune-related genes in the etiology and progression of cirrhosis, intending to explore potential therapeutic targets for this disease. GSE36411 gene expression profiling was extracted from the Gene Expression Omnibus repository (GEO). The transcriptomic data were submitted to Weighted Gene Co-expression Network Analysis (WGCNA) to screen for the presence of key genes, and immune-related genes were filtered by comparison to the InateDB database. Cancer Genome Atlas (TCGA) was included in the study to validate the significant modules generated from WGCNA. The key gene interaction network was constructed using GeneMANIA and Metascape. Kaplan-Meier method and Spearman correlation were used to evaluate the correlation of immune-related genes with prognosis, tumor microenvironment, and immune cell infiltration. Finally, we explored a possible mechanism using gene set enrichment (GSEA) analyses. In total, 2,102 differentially expressed genes (DEGs) were identified from the gene expression profile dataset. A weighted gene co-expression network analysis was performed, resulting in the classification of genes into 3 modules. Among these modules, the turquoise module was found to be most closely associated with cirrhosis. By comparing the turquoise module genes with an InateDB immune-related gene set, we identified 157 immune-associated genes. In addition, our study found that many hub genes are strongly associated with the number of immune-related genes in liver cirrhosis, in addition to a few modules associated with immune infiltration. It turns out that these hub genes were engaged in migration, activation, and immune cell regulation, as well as in the signaling pathways that drive the immune response to infection. Our research offered a deeper understanding of the underlying processes of immune infiltration in cirrhosis and also suggested potential treatment options for this troublesome condition. Our results demonstrate the effectiveness of WGCNA in uncovering new knowledge regarding the biology of cirrhosis and the function of the immune system in this disease. More studies ought to focus on the validation of the identified hub genes and the determination of their clinical relevance. These results could serve as the basis for the creation of more potent therapies for those with liver cancer linked to cirrhosis.

Neoadjuvant docetaxel plus carboplatin vs epirubicin plus cyclophosphamide followed by docetaxel in triple-negative, early-stage breast cancer (NeoCART): Results from a multicenter, randomized controlled, open-label phase II trial.

Previous studies have shown that the addition of carboplatin to neoadjuvant chemotherapy improved the pathologic complete response (pCR) rate in patients suffering from triple-negative breast cancer (TNBC) and patients who obtained a pCR could achieve prolonged event-free survival (EFS) and overall survival (OS). However, no studies have assessed the effects of the combination of docetaxel and carboplatin without anthracycline with taxane-based and anthracycline-based regimens. The NeoCART study was designed as a multicenter, randomized controlled, open-label, phase II trial to assess the efficacy and safety of docetaxel combined with carboplatin in untreated stage II-III TNBC. All eligible patients were randomly assigned, at a 1:1 ratio, to an experimental docetaxel plus carboplatin (DCb) for six cycles group (DCb group) or an epirubicin plus cyclophosphamide for four cycles followed by docetaxel for four cycles group (EC-D group). PCR (ypT0/is ypN0) was evaluated as the primary outcome. Between 1 September 2016 and 31 December 2019, 93 patients were randomly assigned and 88 patients were evaluated for the primary endpoint (44 patients in each group). In the primary endpoint analysis, 27 patients in the DCb group (61.4%, 95% CI 47.0-75.8) and 17 patients in the EC-D group achieved a pCR (38.6%, 95% CI 24.3-53.0; odds ratio 2.52, 95% CI 2.4-43.1; Pnoninferiority = .004). Noninferiority was met, and the DCb regimen was confirmed to be superior to the EC-D regimen (P = .044, superiority margin of 5%). At the end of the 37-month median follow-up period, OS and EFS rates were equivalent in both groups.

Characterization of Fc gamma receptor IIb expression within abdominal aortic aneurysm.

OBJECTIVE: To evaluate protein profiles and Fc gamma receptor IIb (FCGRIIB) expression in abdominal aortic aneurysm (AAA) compared to the expression in normal aortas. METHODS: We performed a protein array to study the protein expression profiles within AAA and normal aortic tissues. FCGRIIB was found to be significantly elevated in AAA samples. Quantitative PCR and Western blot analyses were performed to study the expression of FCGRIIB in AAA compared to that in normal aortic tissue. Immunohistochemistry was used to locate FCGRIIB and the B cell marker CD19 in AAA and normal aortas specimens. RESULTS: FCGRIIB was significantly elevated in AAA tissues in both mRNA (AAA vs. normal control: about 5.8 folds, p < 0.001) and protein levels (AAA vs. normal control: about 6.3 folds, p < 0.001). In AAA specimens, immunohistochemistry revealed that FCGRIIB localized to the area of inflammatory infiltrates, which consisted of CD 19+ B cells and other inflammatory cells. FCGRIIB and CD19 were undetectable in normal aortas. CONCLUSIONS: FCGRIIB was significantly elevated in AAA tissues compared to normal aortas. FCGRIIB may be involved in the pathogenesis of AAA by regulation of inflammatory reactions.

Aspects of digestive anatomy, feed intake and digestion in the Chinese pangolin (Manis pentadactyla) at Taipei zoo.

Pangolins are considered difficult to maintain in zoos, often attributed to problems in feeding management. Taipei Zoo's designation as a wildlife rescue center for Chinese pangolins (Manis pentadactyla) has resulted in long term feeding experience with development of diets that support recovery, maintenance, and reproduction, as well as experimental opportunities to further understand digestive physiology to optimize nutrition. Opportunistic dissection of 10 animals revealed details of the tongue, salivary glands, stomach and gastrointestinal tract (GIT), including confirmation of anatomical differences between Asian and African pangolin species. Length of the total GIT relative to body length (∼ 9:1) was greater than found in domestic carnivores, more similar to omnivorous species. Intake and digestion trials conducted with 4 animals demonstrated that pangolins maintained body weights (BW; 6-9 kg) consuming diets containing 32-40% crude protein, 20-25% crude fat, and 13-28% crude fiber (DM basis). Daily DM intakes ranged from ∼40 to 70 g per animal, with digestible energy intake 51.5-87.5 kcal /kg BW(0.75) /day; pangolins consumed 9.4-15.2 g DM/kg BW(0.75) /day. Dietary energy data support observations of low metabolism and maintenance requirements for this species, similar to values reported for other myrmecophageous species. Addition of 5% ground chitin to diets improved fecal consistency, and decreased digestibility of DM, protein, and energy; addition of chitosan (chitin treated with NaOH) resulted in diet rejection. This information may assist in enhancement of captive diets, as well as in controlling obesity in pangolins.

MCP-1 stimulates MMP-9 expression via ERK 1/2 and p38 MAPK signaling pathways in human aortic smooth muscle cells.

OBJECTIVE: We investigated the molecular mechanism underlying the role of monocyte chemoattractant protein-1 (MCP-1) in the formation and development of human abdominal aortic aneurysm (AAA). METHODS: We examined protein expression profiles using a protein array and found that MCP-1 was the most highly expressed protein in AAA tissues compared with normal aortas. To investigate the potential mechanism of MCP-1 involvement in the pathogenesis of AAA, we treated human aortic smooth muscle cells (HASMCs) with human recombinant MCP-1. RESULTS: MCP-1 was the most highly expressed protein in AAA tissues compared with normal aorta; matrix metalloproteinase-9 (MMP-9) expression was also significantly increased. Treatment with MCP-1 significantly increased the expression and activation of MMP-9 and activated the three major mitogen activated protein kinases (MAPKs) extracellular signal regulated kinase (ERK), c-Jun amino terminal kinase (JNK1/2) and p38 MAPK. Furthermore, MCP-1-induced secretion of MMP-9 was inhibited by U0126 (inhibitor of the ERK 1/2 pathway) and SB203580 (inhibitor of the p38 MAPK pathway), but not SP600125 (inhibitor of the JNK1/2 pathway). CONCLUSION: These data demonstrate that MCP-1 stimulates secretion of MMP-9 directly through the ERK1/2 and p38 MAPK mediated pathways in HASMCs. Thus, inhibition of this molecular mechanism might be a potential therapeutic target in the non-surgical treatment of AAA.

Rational Regulation of Optimal Oxygen Vacancy Concentrations on VO2 for Superior Aqueous Zinc-Ion Battery Cathodes.

VO2 with its special tunnel structure and high theoretical capacity is an ideal candidate for cathode materials for aqueous zinc-ion batteries (ZIBs). However, the slow kinetics and structural instability due to the strong electrostatic interactions between the host structure of VO2 and Zn2+ hinder its application. Defect engineering is a well-recognized strategy for improving the intrinsic ion-electron dynamics and structural stability of this material. However, the preparation of oxygen vacancies poses significant difficulties, and it is challenging to control their concentration effectively. Excessive or insufficient vacancy concentration can have a negative effect on the cathode material. Herein, we propose electrode materials with controlled oxygen vacancies prepared in situ on carbon nanofibers (CNF) by a simple, one-step hydrothermal process (Ov-VO2@CNF). This method can balance the adsorption energy and migration energy barrier easily, and we maximized the adsorption energy of Zn2+ while minimizing the adsorption energy barrier. Notably, the Ov2-VO2@CNF electrode delivered a high specific capacity (over 450 mAh g-1 at 0.1 A g-1) and excellent cycle stability (318 mAh g-1 at 5 A g-1 capacity after 2000 cycles with a capacity retention of 85%). This rational design of precisely regulated defect engineering provides a way to obtain advanced electrode materials with excellent comprehensive properties.

Wet depositions of cations in forests across NADP, EMEP, and EANET monitoring networks over the last two decades.

Studies focused on emissions and acid deposition of sulfur (S) and nitrogen (N) and the consequent precipitation acidity have a long history. However, atmospheric depositions of cations play a critical role in buffering precipitation acidity, and providing cationic nutrients for vegetation growth lacks sufficient studies equally. The spatiotemporal patterns of cation depositions and their neutralization potential across broad scales remain unclear. Through synthesizing the long-term data in forest sites (n = 128) derived from three monitoring networks (NADP in Northern America, EMEP in Europe, and EANET in East Asia) on wet deposition of cations (Na+, NH4-N, K+, Mg2+, and Ca2+), this study assesses the temporal changes and spatial patterns of cation depositions and their neutralization potential over the last two decades. The results showed that the depositions of cationic nutrients were considerably higher in EANET compared to NADP and EMEP. The depositions of sea salt-associated sodium exhibited a significant transition from marine (> 15 kg ha-1 year-1) to inland (< 3.0 kg ha-1 year-1) forest sites attributable to the precipitation quantity and influences of sea spray. The higher emissions of NH3 and particulate matter in East Asia explained the higher cation depositions in EANET than NADP and EMEP. The annual trends of cations revealed that only 20-30% of the forest sites showed significant changing trends and the sites widely spread across the three networks. Possibly, base cation (BC) deposition has reached a low and stable condition in NADP and EMEP, while it has high spatial heterogeneity in the temporal change in EANET. The difference in BC deposition among the three networks reflects their distinct development of economy. Our synthesis indicates that the annual trends of neutralization factor (NF) in NADP can be explained by the declining of acid potential (AP), not by neutralization potential (NP) as BC deposition has been stably low over the past two decades. Whereas, the concurrent decreases of AP and NP in EMEP or plateau period of both AP and NP in EANET have come to a standstill of acid neutralizing capacity.

Dual role of PID1 in regulating apoptosis induced by distinct anticancer-agents through AKT/Raf-1-dependent pathway in hepatocellular carcinoma.

The treatment outcome of hepatocellular carcinoma (HCC) is severely hampered due to its etiology, and thus in depth understanding of the genetic mechanisms underlying response of HCC to various anticancer agents is needed. Here, we have identified Phosphotyrosine interaction domain-containing protein 1 (PID1) as a novel regulator involved in modulation of apoptosis induced by anticancer agents in a context-dependent manner. PID1 relieved chemotherapy-induced ROS production, mitochondrial outer membrane permeability and mitochondrial respiratory depression. In addition, PID1 restricted AKT-mediated inhibition on Raf-1 through interacting with PDPK1 at phosphorylated tyrosine sites, thus enhancing Raf-1-mediated BAD inhibition. Interestingly, AKT, Bcl2 inhibition or Raf-1 silencing abolished PID1-mediated anti-apoptotic effects. However, PID1 altered the rhythmicity of pharmacological activity of Sorafenib on various survival-related kinases, thus resulting in AKT blockade via Raf-1/BRAF/ERK/MEK pathway. BRAF inhibition or Raf-1 depletion disrupted PID1-mediated barrier in AKT activation in response to Sorafenib. Moreover, in vivo study indicated that PID1 deficiency led to increased survival rate upon Doxorubicin treatment but reduced efficacy of Sorafenib. Overall, we propose that PID1 can function as an underlying biomarker of resistance to conventional chemotherapeutic agents but sensitivity towards Sorafenib.

USP3 inhibition is Active Against Chemo-resistant Hepatocellular Carcinoma Anchorage-independent Growth via Suppressing Wnt/ß-catenin.

BACKGROUND: USPs are a family of enzymes that regulate protein degradation, and their dysregulation has been implicated in the development and progression of cancer. AIMS: This study aimed to determine whether ubiquitin-specific proteases 3 (USP3) could be a potential target for therapy in hepatocellular carcinoma (HCC), particularly in resistant HCC. This study systematically investigated the role of USP3 in HCC, with a focus on chemo-resistant HCC cells. METHODS: The level of USP3 from clinical samples was measured using an ELISA assay. Cell proliferation, apoptosis, migration, and anchorage-independent colony formation assays were performed. Transfection was performed to knock down USP3 expression and measure ß-catenin activity, and real-time PCR was used to measure levels of MYC and CYCLIN D1 genes. RESULTS: USP3 protein was upregulated in HCC tissues, but its upregulation was not associated with clinicopathology. USP3 knockdown had a similar inhibitory effect on growth in both sensitive and resistant HCC cells, did not affect migration, and induced apoptosis in sensitive but not resistant HCC cells. Furthermore, USP3 knockdown was more effective in suppressing anchorage-independent colony formation in chemoresistant HCC cells compared to their chemo-sensitive counterparts. Pearson correlation coefficient analysis revealed a strong positive correlation between USP3 and CTNNB1, and consistently, USP3 knockdown reduced the levels and activities of ß-catenin in HCC cells. Using a Wnt activator (lithium) in rescue studies significantly reversed the inhibitory effects of USP3 knockdown. CONCLUSION: The findings suggest that inhibiting USP3 is an effective strategy against cancer stem cells and chemo-resistant HCC cells.

Changes of precipitation acidity related to sulfur and nitrogen deposition in forests across three continents in north hemisphere over last two decades.

Through synthesizing bulk precipitation chemistry in forest sites (n = 128) from three monitoring networks, (NADP in Northern America, EMEP in Europe, and EANET in East Asia), this study quantifies the temporal changes of precipitation acidity and its dominant acidifying agents over the last two decades. Results show distinct declines of sulfate and nitrate depositions and increases of precipitation pH in northeast America and central and east Europe, but not in Asia during 1999 and 2018. The decreases of sulfate and nitrate depositions likely reflect the long-term effort of pollutant emission controls. The temporal pattern of sulfate (SO42-)/nitrate (NO3-) and ammonium nitrogen (NH4-N)/nitrate nitrogen (NO3-N) equivalent ratios indicate that acid rain in the NADP and EMEP have transitioned from sulfate-dominated to nitrate-dominated, and the DIN deposition has shifted from nitrate-dominated to ammonium-dominated in recent years, owing to reductions of sulfur dioxides (SO2) and nitrogen oxides (NOx) emissions. In contrast, sulfate still plays a dominant role on the acidity of precipitation than nitrate in Asia, and NH4-N deposition also has a significant contribution in N flux due to increasing trends of ammonia emissions in Southeast Asia.

Neoadjuvant therapy in triple-negative breast cancer: A systematic review and network meta-analysis.

BACKGROUND: Evidence for the preferred neoadjuvant therapy regimen in triple-negative breast cancer (TNBC) is not yet established. METHODS: Literature search was conducted from inception to February 12, 2022. Phase 2 and 3 randomized controlled trials (RCTs) investigating neoadjuvant therapy for TNBC were eligible. The primary outcome was pathologic complete response (pCR); the secondary outcomes were all-cause treatment discontinuation, disease-free survival or event-free survival (DFS/EFS), and overall survival. Odd ratios (OR) with 95% credible intervals (CrI) were used to estimate binary outcomes; hazard ratios (HR) with 95% CrI were used to estimate time-to-event outcomes. Bayesian network meta-analysis was implemented for each endpoint. Sensitivity analysis and network meta-regression were done. RESULTS: 41 RCTs (N = 7109 TNBC patients) were eligible. Compared with anthracycline- and taxane-based chemotherapy (ChT), PD-1 inhibitor plus platinum plus anthracycline- and taxane-based ChT was associated with a significant increased pCR rate (OR 3.95; 95% CrI 1.81-9.44) and a higher risk of premature treatment discontinuation (3.25; 1.26-8.29). Compared with dose-dense anthracycline- and taxane-based ChT, the combined treatment was not associated with significantly improved pCR (OR 2.57; 95% CrI 0.69-9.92). In terms of time-to-event outcomes, PD-1 inhibitor plus platinum plus anthracycline- and taxane-based ChT was associated with significantly improved DFS/EFS (HR 0.42; 95% CrI 0.19-0.81). CONCLUSIONS: PD-1 inhibitor plus platinum and anthracycline- and taxane-based ChT was currently the most efficacious regimen for pCR and DFS/EFS improvement in TNBC. The choice of chemotherapy backbone, optimization of patient selection with close follow-up and proactive symptomatic managements are essential to the antitumor activity of PD-1 inhibitor.

Badland landscape response to individual geomorphic events.

Landscapes form by the erosion and deposition of sediment, driven by tectonic and climatic forcing. The principal geomorphic processes of badland - landsliding, debris flow and runoff erosion - are similar to those in full scale mountain topography, but operate faster. Here, we show that in the badlands of SW Taiwan, individual rainfall events cause quantifiable landscape change, distinct for the type of rainfall. Typhoon rain reduced hillslope gradients, while lower-intensity precipitation either steepened or flattened the landscape, depending on its initial topography. The steep topography observed in our first survey is inconsistent with the effects of any of the rainfall events. We suggest that it is due to the 2016 Mw 6.4 Meinong earthquake. The observed pattern in the badlands was mirrored in the response of the Taiwan mountain topography to typhoon Morakot in 2009, confirming that badlands offer special opportunities to quantify natural landscape dynamics on observational time scales.

Constraining tectonic uplift and advection from the main drainage divide of a mountain belt.

One of the most conspicuous features of a mountain belt is the main drainage divide. Divide location is influenced by a number of parameters, including tectonic uplift and horizontal advection. Thus, the topography of mountain belts can be used as an archive to extract tectonic information. Here we combine numerical landscape evolution modelling and analytical solutions to demonstrate that mountain asymmetry, determined by the location of the main drainage divide, increases with increasing uplift gradient and advection velocity. Then, we provide a conceptual framework to constrain the present or previous tectonic uplift and advection of a mountain belt from the location and migration direction of its main drainage divide. Furthermore, we apply our model to Wula Shan horst, Northeastern Sicily, and Southern Taiwan.

Peritoneal Metastasis After Treated With Abemaciclib Plus Fulvestrant for Metastatic Invasive Lobular Breast Cancer: A Case Report and Review of the Literature.

Peritoneal metastases from invasive lobular carcinoma (ILC) of breast are uncommon and usually related to poor prognosis due to difficulty of detection in clinical practice and drug resistance. Therefore, recognizing the entities of peritoneal metastases of ILC and the potential mechanism of drug resistance is of great significance for early detection and providing accurate management. We herein report a case of a 60-year-old female who presented with nausea and vomiting as the first manifestation after treated with abemaciclib (a CDK4/6 inhibitor) plus fulvestrant for 23 months due to bone metastasis of ILC. Exploratory laparotomy found multiple nodules in the peritoneum and omentum, and immunohistochemistry confirmed that the peritoneal metastatic lesions were consistent with ILC. Palliative therapy was initiated, but the patient died two months later due to disease progression with malignant ascites. Whole exome sequencing (WES) was used to detect the tumor samples and showed the peritoneal metastatic lesions had acquired ESR1 and PI3KCA mutations, potentially explaining the mechanism of endocrine therapy resistance. We argue that early diagnosis of peritoneal metastasis from breast cancer is crucial for prompt and adequate treatment and WES might be an effective supplementary technique for detection of potential gene mutations and providing accurate treatment for metastatic breast cancer patients.

Adjuvant CDK4/6 inhibitors combined with endocrine therapy in HR-positive, HER2-negative early breast cancer: A meta-analysis of randomized clinical trials.

BACKGROUND: The benefit of adjuvant cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors with endocrine therapy (ET) in hormone receptor-positive, human epidermal growth factor 2 receptor-negative (HR+/HER2-) early breast cancer (EBC) is uncertain. Hence, we performed a meta-analysis to determine the efficacy and safety of adjuvant CDK4/6 inhibitors plus ET and to identify potential preferred subpopulations for this regimen. METHODS: A literature search was conducted in PubMed, Embase, Cochrane databases up to Jan 15, 2021. Hazard ratios (HRs) for invasive disease-free survival (IDFS) and risk ratios (RRs) for grade 3/4 adverse events (AEs) and treatment discontinuation were extracted. Analysis with predefined subgroup variables was done. Trial sequential analysis (TSA) was performed to assess the conclusiveness of survival outcomes. RESULTS: Three trials were eligible (N = 12647). Compared with ET, adjuvant CDK4/6 inhibitors with ET prolonged IDFS in patients with HR+/HER2- EBC (HR 0.87, 95% CI 0.76-0.98, p = 0.03, I2 = 19%), with positive therapeutic responses observed in patients with N2/N3 nodal status (HR 0.83, 95% CI 0.71-0.97, p = 0.02, I2 = 0%). None of the cumulative z-curves crossed the trial monitoring boundaries in TSA, and no reliable conclusion could be drawn. The combination treatment carried a higher risk of grade 3/4 AEs (RR 4.14, 95% CI 3.33-5.15, p < 0.00001) and an increase in treatment discontinuation due to AEs (RR 19.16, 95% CI 9.27-39.61, p < 0.00001). CONCLUSIONS: Adjuvant CDK4/6 inhibitors with ET might provide survival benefit in HR+/HER2- EBC. A statistically significantly improved IDFS was only observed in N2/N3 subgroup. However, overall evidence favoring the use of this combination regimen was inadequate.

Tumor Microenvironment Characterization in Breast Cancer Identifies Prognostic and Neoadjuvant Chemotherapy Relevant Signatures.

Immune response which involves distinct immune cells is associated with prognosis of breast cancer. Nonetheless, less study have determined the associations of different types of immune cells with patient survival and treatment response. In this study, A total of 1,502 estrogen receptor(ER)-negative breast cancers from public databases were used to infer the proportions of 22 subsets of immune cells. Another 320 ER-negative breast cancer patients from Guangdong Provincial People's Hospital were also included and divided into the testing and validation cohorts. CD8+ T cells, CD4+ T cells, B cells, and M1 macrophages were associated with favourable outcome (all p <0.01), whereas Treg cells were strongly associated with poor outcome (p = 0.005). Using the LASSO model, we classified patients into the stromal immunotype A and B subgroups according to immunoscores. The 10 years OS and DFS rates were significantly higher in the immunotype A subgroup than immunotype B subgroup. Stromal immunotype was identified as an independent prognostic indicator in multivariate analysis in all cohorts and was also related to pathological complete response(pCR) after neoadjuvant chemotherapy. The nomogram that integrated the immunotype and clinicopathologic features showed good predictive accuracy for pCR and discriminatory power. The stromal immunotype A subgroup had higher expression levels of immune checkpoint molecules (PD-L1, PD-1, and CTLA-4) and cytokines (IL-2, INF-γ, and TGF-ß). In addition, patients with immunotype A and B diseases had distinct mutation signatures. Therefore, The stromal immunotypes could predict survival and responses of ER-negative breast cancer patients to neoadjuvant chemotherapy.

Anthracycline-containing versus carboplatin-containing neoadjuvant chemotherapy in combination with trastuzumab for HER2-positive breast cancer: the neoCARH phase II randomized clinical trial.

BACKGROUND: Although dual blockade HER2-based neoadjuvant chemotherapy is associated with excellent outcomes for human epidermal growth factor receptor 2 (HER2)-positive breast cancer, pertuzumab is not available to all patients due to cost. The optimal neoadjuvant chemotherapy for HER2-positive breast cancer in the presence of a single HER2 blockade is unknown. This study aimed to compare the efficacy and safety of epirubicin/cyclophosphamide followed by docetaxel/trastuzumab (EC-TH) with docetaxel/carboplatin/trastuzumab (TCH) neoadjuvant setting for HER2-positive breast cancer under the single HER2 blockade. METHODS: Patients with stage II-IIIC HER2-positive breast cancer were randomly assigned to either eight cycles of EC-TH every 3 weeks during all chemotherapy cycles, or six cycles of TCH every 3 weeks. The primary endpoint was pathological complete response (pCR) (defined as the absence of invasive tumor cells in breast and axilla, ypT0/is ypN0). RESULTS: From May 2017 to November 2019, 140 patients were randomly assigned, and 135 patients were ultimately found evaluable for the primary endpoint. The pCR was recorded in 25 of 67 patients [37.3%; 95% confidence interval (CI), 25.8-50.0] in the EC-TH group and in 38 of 68 patients (55.9%, 95% CI, 43.3-67.9) in the TCH group (p = 0.032). The most common adverse events (AEs) were neutropenia in 24 of 67 (35.8%) patients in the EC-TH group versus 27 of 68 (39.7%) in the TCH group (p = 0.642), anemia in 33 of 67 (49.3%) patients in the EC-TH group versus 34 of 68 (50.0%) in the TCH group (p = 0.931), and thrombocytopenia in five of 67 (7.5%) patients in the EC-TH group versus 17 of 68 (25.0%) in the TCH group (p = 0.006). CONCLUSION: For patients receiving the single HER2 blockade trastuzumab for HER2-positive breast cancer, TCH regimen might be a preferred neoadjuvant therapy. TRIAL REGISTRATION: This trial was registered with ClinicalTrials.gov identifier: NCT03140553) on 2 May 2017.

Prevalence of epilepsy and alcohol-related risk in Zayul County, Tibet Autonomous Region in China: an initial survey.

OBJECTIVE: The goal of this study was to establish the prevalence rates of epilepsy and alcohol-related risk and the treatment gap in Zayul County, Tibet Autonomous Region, to evaluate the diagnosis and treatment status of these patients. METHODS: A door-to-door epidemiological survey was conducted among all the people living in the towns of Shang Zayul and Xia Zayul. A screening questionnaire for epilepsy was used. Clinical and sociodemographic data were collected from patients confirmed to have epilepsy. An audit was used for patients with epilepsy who had a definite history of alcohol consumption and drinking habit change. RESULTS: A total of 7669 people were investigated. Of these, 180 were confirmed to have epilepsy, which was active in 175. Lifetime prevalence was estimated to be 23.5 per 1000 in this population. None of the patients with active epilepsy had received any reasonable antiepileptic therapy in the week before the survey (treatment gap). Ninety-six percent of patients with epilepsy aged between 20 and 60 drank alcoholic beverages. However, in only 25 (13.9%) patients with epilepsy was the epilepsy related to alcohol; most patients (80.6%) had no definite causes. There were no local health workers who received any formal training on epilepsy before, nor did the local health agencies provide any conventional antiepileptic drugs. CONCLUSION: The prevalence rates of epilepsy in the towns of Shang Zayul and Xia Zayul of the Tibet Autonomous Region were relatively higher than in other areas. The alcohol-related health problems cannot be ignored. This serious situation and the large treatment gap indicate a pressing need for medical, financial and social support in this population.

The deubiquitinase USP25 supports colonic inflammation and bacterial infection and promotes colorectal cancer.

Bacterial infection or abnormal colonization in the gastrointestinal system is associated with subsets of inflammatory bowel disease and colorectal cancer. Here we demonstrated essential roles of ubiquitin-specific protease 25 (USP25) in experimental colitis, bacterial infections and colon cancer. Knockout or pharmacologic inhibition of USP25 potentiated immune responses after induction of experimental colitis or bacterial infections that promoted clearance of infected bacteria and resolution of inflammation and attenuated Wnt and SOCS3-pSTAT3 signaling, which inhibited colonic tumorigenesis. USP25 levels were positively or negatively correlated with Fusobacterium nucleatum colonization and ß-catenin levels or SOCS3 levels in human colorectal tumor biopsies, respectively, and predicted poor prognosis of patients with cancers in the gastrointestinal system. Our findings suggest USP25 as a promoter and druggable target for gastrointestinal infections and cancers.

The role of adjuvant chemotherapy in stage I-III male breast cancer: a SEER-based analysis.

BACKGROUND AND AIMS: Male breast cancer is an uncommon disease. The benefit of adjuvant chemotherapy in the treatment of male breast cancer patients has not been determined. The aim of this study was to explore the value of adjuvant chemotherapy in men with stage I-III breast cancer, and we hypothesized that some male patients may safely skip adjuvant chemotherapy. METHODS: Male breast cancer patients between 2010 and 2015 from the Surveillance Epidemiology and End Results database were included. Univariate and multivariate Cox analyses were used to analyse the factors associated with survival. The propensity score matching method was adopted to balance baseline characteristics. Kaplan-Meier curves were used to evaluate the impacts of adjuvant chemotherapy on survival. The primary endpoint was survival. RESULTS: We enrolled 514 patients for this study, including 257 patients treated with chemotherapy and 257 patients without. There was a significant difference in overall survival (OS) but not in breast cancer-specific survival (BCSS) between the two groups (p < 0.001 for OS and p = 0.128 for BCSS, respectively). Compared with the non-chemotherapy group, the chemotherapy group had a higher 4-year OS rate (97.5% versus 95.2%, p < 0.001), while 4-year BCSS was similar (98% versus 98.8%, p = 0.128). The chemotherapy group had longer OS than the non-chemotherapy group among HR+, HER2-, tumour size >2 cm, lymph node-positive male breast cancer patients (p < 0.05). Regardless of tumour size, there were no differences in OS or BCSS between the chemotherapy and non-chemotherapy cohorts for lymph node-negative patients (OS: p > 0.05, BCSS: p > 0.05). Adjuvant chemotherapy showed no significant effects on both OS and BCSS in patients with stage I (OS: p = 0.100, BCSS: p = 0.858) and stage IIA breast cancer (OS: p > 0.05, BCSS: p > 0.05). CONCLUSION: For stage I and stage IIA patients, adjuvant chemotherapy could not improve OS and BCSS. Therefore, adjuvant chemotherapy might be skipped for stage I and stage IIA male breast cancer patients.