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Despite significant improvement in therapeutic development in the past decades, breast cancer remains a formidable cause of death for women worldwide. The hormone positive subtype (HR(+)) (also known as luminal type) is the most prevalant category of breast cancer, comprising ~70% of patients. The clinical success of the three CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib has revolutionized the treatment of choice for metastatic HR(+) breast cancer. Accumulating evidence demonstrate that the properties of CDK4/6 inhibitors extend beyond inhibition of the cell cycle, including modulation of immune function, sensitizing PI3K inhibitors, metabolism reprogramming, kinome rewiring, modulation of the proteosome, and many others. The ubiquitin-proteasome pathway (UPP) is a crucial cellular proteolytic system that maintains the homeostasis and turnover of proteins.We performed transcriptional profiling of the HR(+) breast cancer cell lines MCF7 and T47D treated with Palbociclib. Differential expressed genes were analyzed for novel pathways enriched. The results were further validated with biochemical assays and with real world clinical database cohorts.We uncovered a novel mechanism that demonstrate the CDK4/6 inhibitors suppress the expression of three ubiquitin conjugating enzymes UBE2C, UBE2S, UBE2T. Further validation in the HR(+) cell lines show that Palbociclib and ribociclib decrease UBE2C at both the mRNA and protein level, but this phenomenon was not shared with abemaciclib. These three E2 enzymes modulate several E3 ubiquitin ligases, including the APC/C complex which plays a role in G1/S progression. We further demonstrate the UBE2C/UBE2T expression levels are associated with breast cancer survival, and HR(+) breast cancer cells demonstrate dependence on the UBE2C.Our study suggests a novel link between CDK4/6 inhibitor and UPP pathway, adding to the potential mechanisms of their clinical efficacy in cancer.

Deleterious germline BRCA1/2 mutations are among the most highly pathogenic variants in hereditary breast and ovarian cancer syndrome. Recently, genes implicated in homologous recombination repair (HRR) pathways have been investigated extensively. Defective HRR genes may indicate potential clinical benefits from PARP (poly ADP ribose polymerase) inhibitors beyond BRCA1/2 mutations.We evaluated the prevalence of BRCA1/2 mutations as well as alterations in HRR genes with targeted sequencing. A total of 648 consecutive breast cancer samples were assayed, and HRR genes were evaluated for prevalence in breast cancer tissues.Among 648 breast cancers, there were 17 truncating and 2 missense mutations in BRCA1 and 45 truncating and 1 missense mutation in BRCA2, impacting 3% and 5% of the study population (collectively altered in 6%) with cooccurrence of BRCA1/2 in 7 breast cancers. On the other hand, HRR genes were altered in 122 (19%) breast cancers, while TBB (Talazoparib Beyond BRCA) trial-interrogated genes (excluding BRCA1/2) were mutated in 107 (17%) patients. Beyond BRCA1/2, the most prevalent HRR mutant genes came from ARID1A (7%), PALB2 (7%), and PTEN (6%). Collectively, 164 (25%) of the 648 Taiwanese breast cancer samples harbored at least one mutation among HRR genes.The prevalence of BRCA1/2 mutations was far below one tenth, while the prevalence of HRR mutations was much higher and approached one-fourth among Taiwanese breast cancers. Further opportunities to take advantage of defective HRR genes for breast cancer treatment should be sought for the realization of precision medicine.

Breast cancer is one of the leading causes of cancer death in women, and although treatment outcome has substantially improved in the past decades, advanced or metastatic breast cancers still carry a poor prognosis. Gene amplification is one of the frequent genetic alterations in cancer, and oncogene amplification may be associated with cancer aggressiveness and oncogenicity. Targeting amplified genes such as HER2 has vastly improved disease outcome and survival, and anti-HER2 therapeutics have revolutionized the standard of care in HER2 breast cancer. Besides currently known druggable gene amplifications including ERBB2 and FGFR2, other frequently amplified genes are relatively less well known for function and clinical significance. By querying 4 large databases from TCGA and AACR-Genie, from a total of 11,890 patients with invasive ductal breast carcinoma, we discover IKZF3, CCND1, ERBB2 to be consistently amplified across different cohorts. We further identify IKZF3 as a frequently amplified gene in breast cancer with a prevalence of 12–15% amplification rate. Interestingly, IKZF3 amplification is frequently co-amplified with ERBB2/HER2, and is also associated with worse prognosis compared to IKZF3 non-amplified cancers. Analysis of HER2 breast cancer patients treated with trastuzumab revealed decrease in both ERBB2/HER2 and IKZF3 expression. Further investigation using the DepMap for gene dependency by genome wide CRISPR screening revealed dependence on IKZF3 in HER2 breast cancer cell lines. Our study utilized an integrative analysis of large scale patient genomics, transcriptomics and clinical data to reveal IKZF3 as a frequently amplified gene, and suggest a potential role of IKZF3 as a druggable target for HER2 breast cancer.

Our study aimed to (i) utilize novel electrical cardiometry and observe acute changes in cardiac biomarkers among 24-h and 48-h ultra-marathoners, and (ii) examine whether alterations in cardiac responses were associated with the average running speed of these participants. Twenty-four 24-h and sixteen 48-h ultra-marathoners were recruited. Electrical cardiometry in the 2 groups showed significant post-race drops in systolic pressure (24-h: p=0.001; 48-h: p=0.016) and rapid increases in heart rate (24-h, p=0.004; 48-h, p=0.001). Cardiac output increased in 48-h runners (p=0.012) and stroke volume decreased in 24-h runners (p=0.009) at post-test. Six of 20 (30%) 24-h and 4 of 16 (25%) 48-h runners had high-sensitivity troponin T values above the reference interval after the races. N-terminal proB-type natriuretic peptide levels showed a 15-fold increase in 24-h runners and a 10-fold increase in 48-h runners at post-race. There was a positive correlation between delta N-terminal proB-type natriuretic peptide and running mileage (Our study aimed to (i) utilize novel electrical cardiometry and observe acute changes in cardiac biomarkers among 24-h and 48-h ultra-marathoners, and (ii) examine whether alterations in cardiac responses were associated with the average running speed of these participants. Twenty-four 24-h and sixteen 48-h ultra-marathoners were recruited. Electrical cardiometry in the 2 groups showed significant post-race drops in systolic pressure (24-h: p=0.001; 48-h: p=0.016) and rapid increases in heart rate (24-h, p=0.004; 48-h, p=0.001). Cardiac output increased in 48-h runners (p=0.012) and stroke volume decreased in 24-h runners (p=0.009) at post-test. Six of 20 (30%) 24-h and 4 of 16 (25%) 48-h runners had high-sensitivity troponin T values above the reference interval after the races. N-terminal proB-type natriuretic peptide levels showed a 15-fold increase in 24-h runners and a 10-fold increase in 48-h runners at post-race. There was a positive correlation between delta N-terminal proB-type natriuretic peptide and running mileage (

Aim Lung cancer is typically categorized into small cell lung cancer (SCLC) and non–small cell lung cancer (NSCLC). NSCLC comprises of the majority of lung cancer with a poor prognosis in advanced cases. Transcriptional profiling studies, including microarrays and RNA-sequencing studies, have significantly enriched our knowledge of gene expression patterns in NSCLC. A recent transcriptional profiling study identified high prevalence of CBX3/HP1-gamma upregulation in human NSCLC samples. CBX3/HP1-gamma is an isoform of the heterochromatin protein 1 family, which plays a role in heterochromatin formation and is linked to cancer. Methods We examined lung cancer samples from our hospital using immunohistochemistry for CBX3/HP1-gamma staining. We also analyzed publicly available databases of NSCLC transcriptional profiling to validate our results. Results We identified a high prevalence (77.2%) of samples with positive CBX3/HP1-gamma staining by immunohistochemistry in NSCLC patient samples. Independently, we queried a publicly available dataset (GSE40419) containing RNA-seq data from 77 patients. Upregulation of CBX3/HP1-gamma in tumor samples was present in 60.2% of the patients. A similar correlation was also observed in the The Cancer Genome Atlas (TCGA) database. Interestingly, we discovered a highly significant association between positive CBX3/HP1-gamma staining and EGFR mutation in our patient samples (40 of 42 patients, P

Lung cancer is one of the leading causes of death from cancer worldwide, with a poor prognosis in advanced cases. In the past decade, epidermal growth factor receptor (EGFR) inhibitors have shown significant efficacy towards treatment for EGFR mutant lung cancer. Expanding our knowledge of oncogenic EGFR signaling pathways is therefore of highly importance for the cancer field. Recently it has been proposed that mutant EGFR transcriptionally silences the TET1 (ten-eleven translocation methylcytosine dioxygenase 1) gene in cellular and animal models of lung cancer. Since TET1 is a known DNA demethylase, EGFR-mediated TET1 silencing therefore downregulates demethylation of tumor suppressor genes, which then leads to tumor growth inhibition, potentiating the role of TET1 as a tumor suppressor gene in NSCLC. In our study, we examined the role of EGFR-TET1 silencing in NSCLC patient samples. By independently analyzing the TCGA (The Cancer Genome Atlas) NSCLC data set as well as a cohort of patient samples from our hospital and a data set from publicly deposited databases, we did not observe the aforementioned mutant EGFR silencing of TET1. Conversely, in our cohort, TET1 expression levels were significantly elevated in EGFR mutant samples (P=0.007). Patients with higher TET1 levels showed a trend of better response rates to EGFR inhibitors compared to low TET1 staining levels, although the result was not significant (P=0.08). Furthermore, we did not observe a correlation between TET1 expression levels and patient survival. We conclude that while oncogenic EGFR suppression of TET1 is established in cellular and animal models of lung cancer, its role in patient outcome and prognosis remains inconclusive and warrants further investigation.

Introduction Acute pancreatitis (AP) is a common illness with varied mortality and morbidity. Patients with AP complicated with acute renal failure (ARF) have higher mortality than patients with AP alone. Although ARF has been proposed as a leading mortality cause for AP patients admitted to the ICU, few studies have directly analyzed the relationship between AP and ARF. Methods We performed a retrospective study using the population-based database from the Taiwan National Health Insurance Research Database (NHIRD). In the period from 1 January 2005 to 31 December 2005, every patient with AP admitted to the ICU was included and assessed for the presence of ARF and mortality risk. Results In year 2005, there were a total of 221,101 admissions to the ICU. There were 1,734 patients with AP, of which 261 (15.05%) patients also had a diagnosis of ARF. Compared to sepsis and other critical illness, patients with AP had a higher risk of having a diagnosis of ARF, and patients with both diagnoses had a higher mortality rate in the same ICU hospitalization. Conclusion AP is associated with a higher risk of ARF, and, when both conditions exist, a higher risk of mortality is present.

Hip fracture is an important health care issue in the elderly. Postoperative pulmonary complications occur in 4% of patients after hip fracture surgery. However, previous research is limited regarding pulmonary rehabilitation in this group. In this study, we present clinical evidence regarding the impact of a comprehensive pulmonary rehabilitation program in elderly hip fracture patients after hip surgery. We designed a nonrandomized, Quasi-experimental study, comparing 2 sequential time periods in the same center. Elderly patients (≥65 years) with a new hip fracture from February 1, 2014 to December 31, 2015 and who were willing to undergo a postoperative pulmonary rehabilitation program were enrolled. The pulmonary rehabilitation program started on January 1, 2015. Patients who refused rehabilitation or did not receive a surgical intervention were excluded. Patients received either standard care (standard care group) or standard care plus the postoperative rehabilitation program (intervention group). A total of 240 patients (163 women and 77 men) were enrolled, including 138 in the standard care group and 102 in the intervention group. The intervention group had a significantly lower incidence of pneumonia (6 patients, 5.9%) compared to the standard care group (19 patients, 13.9%). An age >80 years, cancer status, and not undergoing the postoperative pulmonary rehabilitation program were factors associated with a higher risk of pneumonia. In multivariate analysis, age >80 years, history of stroke/cancer, thrombocytopenia, and hyperglycemia (>200 mg/dL) were identified as risk factors for pneumonia. The incidence of pneumonia was lower in the elderly patients with hip fractures who received the postoperative pulmonary rehabilitation program after surgery. This is the first trial to demonstrate the effect of a postoperative pulmonary rehabilitation program in hip surgery patients.

We report a case of acute interstitial pneumonitis and respiratory failure occurring in a 69-year-old, previously healthy patient receiving FOLFOX regimen plus cetuximab for colon cancer. Association between this chemotherapy regimen and interstitial pneumonitis is rarely reported in the literature. We treated the patient with pulse steroid therapy, and improvement in respiratory function and decreased pulmonary infiltrations demonstrated good response to steroids use. However, the patient ultimately expired from respiratory complications after 98 days from admission, possibly due to secondary infection. Both oxaliplatin and cetuximab have rarely been associated with interstitial pneumonitis, and our case may serve as an important reference for physicians notice in patients receiving these chemotherapeutic agents.

We report a case of a 66-year-old Taiwanese female patient with situs ambiguus diagnosed of pancreatic head cancer. She was treated with gemcitabine and erlotinib and remained in stable disease on follow-up imaging studies. Situs ambiguus is a rare disease and reports of such patients with cancer have rarely been reported in the literature. Our case illustrates that standard chemotherapy in this group of patients may be undergone with promising results.

Xeroderma pigmentosum group D (XPD) participates in DNA unwinding during nucleotide excision repair, which may alter the efficacy of platinum-based chemotherapy. We analyzed the influence of codon 751 LysGln polymorphism of XPD on its protein expression levels, clinico-pathological features, and outcome of 188 Chinese patients with metastatic colorectal carcinoma (CRC) that had been treated with first-line Oxaliplatin + Leucovorin + 5-Fluorouracil (FOLFOX-4) chemotherapy. The results showed that in comparison with Caucasian populations, a remarkably lower prevalence of Lys/Gln genotype was noted (16%, n = 30). No between-group difference in XPD protein expression of patients with or without this polymorphism was noted (56.5%vs 59.7%; P = 0.783). Patients with Gln751 allele have a significantly lower response to FOLFOX-4 treatment (36.7%vs 58.2%, P = 0.03), and shorter progression-free (7 vs 11 months; P

Rationale and Objectives To assess the necessity of intravenous contrast medium for abdominopelvic computed tomography (CT) diagnosis of acute appendicitis (APP) among adult patients with right lower quadrant (RLQ) abdominal pain at emergency department (ED). Materials and Methods ED patients with clinical suspicion of APP from RLQ pain for a period of 8 months were enrolled retrospectively. Both pre- and postintravenous contrast-enhanced CT scans were performed for these patients. The visibility of vermiform appendix and specific CT findings of APP were recorded separately for noncontrast CT (NCT) and contrast-enhanced CT (CCT) images without knowledge of the patient's identity and final diagnosis. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of CT diagnosis for APP were compared between the two groups. The ease of identifying appendix was also compared. Results Forty-two (42.0%) of the 100 patients (55 males, 45 females; age range, 16–90 years; mean age, 49.3 years) were APP. There was no significant difference for the visibility of appendix (94% vs. 91%; P = .589) and radiological characters between the CCT and NCT groups. There were significant differences between the two groups for sensitivity (100% vs. 90.5%; P = .036), specificity (94.8% vs. 100%; P = .038), PPV (93.3% vs. 100%; P = .021), NPV (100% vs. 93.5%; P = .021), but no significant difference for accuracy (97% vs. 96%; P = 1). The appendix was easier to detect on CCT than NCT images ( P = .013). Conclusion The diagnostic sensitivity of CCT was significantly better than that of NCT. Intravenous contrast administration could also make doctors easier in indentifying appendixes.

An 84-year-old woman with a past history of type 2 diabetes was admitted to our hospital due to fever and worsening dyspnoea. Chest computed tomography (CT) revealed right middle lobe pneumonia with left pleural effusion (figure 1A). She was intubated because of suspected acute respiratory distress syndrome (ARDS) and treated with 100% oxygen, low tidal volume of 6 ml/kg, and high positive end expiratory pressure (PEEP) of 22 cm H2O with peak inspiratory pressure (PIP) of 30 cm H2O. Unfortunately, 2 weeks after admission, diffuse subcutaneous emphysema was noted. Chest CT (figure 1B) revealed extensive pneumomediastinum and extensive subcutaneous emphysema. PEEP was discontinued and conservative treatment with oxygen therapy and sedation was implemented. …

Background/Purpose Readmission to the intensive care unit (ICU) results in increased consumption of medical resources and costs, and has been proposed as a marker for quality of care. ICU readmission rates have been estimated at 4–14% and different risk factors have been proposed by various studies. Methods Every admission event to the ICU was recorded and readmission episodes were analyzed using a population-based database from the Taiwan National Health Insurance Research Database (NHIRD) for the period from January 1, 2006 to December 31, 2006. Results The average follow-up time was 206.35 days. From the database of 192,201 patients admitted to the ICU, 25,263 patients were re-admitted, with a readmission rate of 13.13%. The leading etiologies for readmission were identified. Using multivariate analysis, age > 39 years old, female gender, ischemic heart disease, lung related disorders, pneumonia, cerebrovascular disease, sepsis, heart failure, chronic liver disease, diabetes mellitus, and chronic obstructive pulmonary disease were identified as significant risk factors for readmission to the ICU. Conclusion This study uses a novel approach to assess risk factors for readmission to the ICU. Higher risk patients should be assessed more carefully before discharge or transfer from the ICU to prevent readmission episodes.