Klotho Regulates Cigarette Smoke-Induced Autophagy: Implication in Pathogenesis of COPD

Introduction

Chronic obstructive pulmonary disease is a progressive lung disease characterized by abnormal cellular responses to cigarette smoke, resulting in tissue destruction and airflow limitation. Autophagy is a fundamental cellular process that eliminates long-lived proteins and damaged organelles through lysosomal degradation pathway, though its role in human diseases remains unclear. We hypothesized that an anti-aging protein, Klotho plays an important role in regulating autophagy in response to cigarette smoke (CS).

Methods

Autophagy was measured by detecting LC3-I and LC3-II expressions. The regulation of autophagy expression by cigarette smoke extract (CSE) was studied in vitro, and small-interfering RNA (siRNA) and recombinant Klotho were employed to investigate the role of Klotho on CSE-induced autophagy. Protein levels and phosphorylation were measured by Western blot assay.

Results

CS exposure resulted in induction of autophagy in alveolar macrophages. Pretreatment of cells with Klotho attenuated CS-induced autophagy whereas knockdown of Klotho augmented CS-induced autophagy. Klotho inhibited phosphorylation of ERK, Akt, and IGF-1 in CSE-stimulated cells.

Conclusions

These data suggest that Klotho plays a critical role in the regulation of CS-induced autophagy and have important implications in understanding the mechanisms of CS-induced cell death and senescence.

     

Perturbations of the anti-ageing hormone Klotho in patients with type 1 diabetes and microalbuminuria

Aims/hypothesis

Patients with type 1 diabetes and microalbuminuria are at high risk of cardiovascular disease (CVD) and end-stage renal disease. Soluble Klotho is an anti-ageing circulating hormone involved in phosphate metabolism and vascular homeostasis through protective effects on the endothelium and antioxidant actions. The role of soluble Klotho in patients with type 1 diabetes and microalbuminuria is unknown.

Methods

In a cross-sectional single-centre study we evaluated the levels of circulating serum soluble Klotho in 33 participants with type 1 diabetes and a history of microalbuminuria (receiving renin–angiotensin system [RAS] inhibitors) and 45 participants with type 1 diabetes without a history of microalbuminuria (not receiving RAS or other antihypertensive drugs). All participants had an eGFR >45 ml/min, duration of diabetes >20 years and no history of CVD. Serum soluble Klotho levels were measured by a validated immunoassay.

Results

Participants with microalbuminuria had significantly lower levels of serum Klotho compared with those without microalbuminuria (median [interquartile range], 659.3 [525.3, 827.6] vs 787.7 [629.5, 1007]; p?=?0.023). This difference persisted after adjustment for variables including age and eGFR. In a subgroup of 30 individuals with and without microalbuminuria, other markers of phosphate balance were not significantly different.

Conclusions/interpretation

In individuals with type 1 diabetes, microalbuminuria is associated with soluble Klotho deficiency. Further studies are required to determine whether soluble Klotho is causally related to the development of cardio-renal disease in type 1 diabetes.

     

Characteristics of urinary and serum soluble Klotho protein in patients with different degrees of chronic kidney disease

Background

Klotho is a single-pass transmembrane protein, which appears to be implicated in aging. The purpose of the present study was to characterize the relationship between the soluble Klotho level and renal function in patients with various degrees of chronic kidney disease (CKD).

Methods

The levels of soluble Klotho in the serum and urine obtained from one hundred thirty-one CKD patients were determined by a sandwich enzyme-linked immunosorbent assay system.

Results

The amount of urinary excreted Klotho during the 24 hr period ranged from 1.6 to 5178 ng/day (median 427 ng/day; interquartile range [IR] 56.8-1293.1), and the serum Klotho concentration ranged from 163.9 to 2123.7 pg/ml (median 759.7 pg/ml; IR 579.5-1069.1). The estimated glomerular filtration rate (eGFR) was significantly correlated with the log-transformed values of the amount of 24 hr urinary excreted Klotho (r?=?0.407, p?<?0.01) and the serum Klotho levels (r?=?0.232, p?<?0.01). However, a stepwise multiple regression analysis identified eGFR to be a variable independently associated only with the log-transformed value of the amount of 24-hr urinary excreted Klotho but not with the log-transformed serum Klotho concentration. Despite the strong correlation between random urine protein-to-creatinine ratio and the 24 hr urinary protein excretion (r?=?0.834, p?<?0.01), a moderate linear association was observed between the log-transformed value of the amount of 24 hr urinary excreted Klotho and that of the urinary Klotho-to-creatinine ratio (Klotho/Cr) in random urine specimens (r?=?0.726, p?<?0.01).

Conclusions

The amount of urinary Klotho, rather than the serum Klotho levels, should be linked to the magnitude of the functioning nephrons in CKD patients. The use of random urine Klotho/Cr as a surrogate for the amount of 24-hr urinary excreted Klotho needs to be evaluated more carefully.

     

Overexpression of Protein Phosphatase 1γ (PP1γ) Is Associated with Enhanced Cell Proliferation and Poor Prognosis in Hepatocellular Carcinoma

Background

Protein phosphatase 1γ (PP1γ), as a member of the protein phosphatase 1 family, may be involved in regulation of multiple cellular processes, such as mitosis, cell survival, and apoptosis. However, little is known about the underlying mechanisms by which PP1γ regulates hepatocellular carcinoma development.

Aim

We investigated the expression profile of PP1γ in hepatocellular carcinoma (HCC) cell lines and human HCC specimens, as well as its potential prognostic significance in HCC.

Methods

PP1γ expression profile was detected in 94 HCC specimens using immunohistochemistry. PP1γ levels in HCC cells were downregulated by small interfering RNA (siRNA) transfection. Cell cycle progression and proliferation status of HCC cells and the effectiveness of doxorubicin were evaluated by flow cytometry and CCK-8 assay. The levels of PP1γ, CyclinD1, PCNA, Mdmx, p53, p21, and active caspase-3 were evaluated by Western blot analysis.

Results

PP1γ was upregulated in tumorous specimens, compared with adjacent nontumorous tissues. Univariate and multivariate survival analyses were conducted to determine the prognostic significance of PP1γ in HCC. The expression pattern of PP1γ was positively correlated with tumor size, histological grade, Ki-67 expression, and poor prognosis in HCC. In addition, depletion of PP1γ by siRNA could inhibit cell proliferation, resulted in G1 phase arrest, and attenuated resistance to doxorubicin in Huh7 cells.

Conclusions

PP1γ is upregulated in HCC cell lines and HCC specimens, promotes cancer cell proliferation through regulation of p53, and may be a potential target for treatment of HCC.

     

Establishing a General Medical Outpatient Clinic for Cancer Survivors in a Public City Hospital Setting

INTRODUCTION

Many cancer centers and community hospitals are developing novel models of survivorship care. However, few are specifically focused on services for socio-economically disadvantaged cancer survivors.

AIMS

To describe a new model of survivorship care serving culturally diverse, urban adult cancer patients and to present findings from a feasibility evaluation.

SETTING

Adult cancer patients treated at a public city hospital cancer center.

PROGRAM DESCRIPTION

The clinic provides comprehensive medical and psychosocial services for patients within a public hospital cancer center where they receive their oncology care.

PROGRAM EVALUATION

Longitudinal data collected over a 3-year period were used to describe patient demographics, patient needs, and services delivered. Since inception, 410 cancer patients have been served. Demand for services has grown steadily. Hypertension was the most frequent comorbid condition treated. Pain, depression, cardiovascular disease, hyperlipidemia, and bowel dysfunction were the most common post-treatment problems experienced by the patients. Financial counseling was an important patient resource.

DISCUSSION

This new clinical service has been well-integrated into its public urban hospital setting and constitutes an innovative model of health-care delivery for socio-economically challenged, culturally diverse adult cancer survivors.

     

Metachronous colorectal cancer

Aim

In this study, we present our patients with metachronous colorectal cancer.

Patients and methods

In the period between 1990 and 2009, 670 patients with colorectal cancer were treated.

Results

Metachronous cancer was developed in 4 (0.6%) patients. The time interval between index and metachronous cancer was 28 months to 22 years (mean 146 months).

Conclusion

Metachronous colorectal cancer is a potential risk that proves the necessity of postoperative colonoscopic control of all patients with colorectal cancer.

     

Stereotactic Ablative Radiotherapy (SABR/SBRT) for Hepatocellular Carcinoma

Purpose of Review

Liver-directed SABR (stereotactic ablative body radiotherapy) is emerging as an effective local therapy option for HCC (hepatocellular carcinoma). This review summarizes recent clinical progresses and proposes future directions.

Recent Findings

SABR is an effective and safe, non-invasive local therapy option for HCC in the primary and salvage treatment settings, as well as a bridge to liver transplantation in selected patients. Randomized trials comparing SABR with other locoregional modalities are currently ongoing.

Summary

Research efforts are being made toward better predicting normal tissue toxicity and tumor radiosensitivity for a tailored maximal safe treatment in HCC SABR. More recently, potential synergy with immunotherapies is of increasing interest in HCC.

     

Cancer Risk Communication with Low Health Literacy Patients: A Continuing Medical Education Program

BACKGROUND

Low health literacy (HL) is an important risk factor for cancer health disparities.

OBJECTIVE

Describe a continuing medical education (CME) program to teach primary care physicians (PCP) cancer risk communication and shared decision-making (SDM) with low HL patients and baseline skills assessment.

DESIGN

Cluster randomized controlled trial in five primary care clinics in New Orleans, LA.

PARTICIPANTS

Eighteen PCPs and 73 low HL patients overdue for cancer screening.

INTERVENTION

Primary care physicians completed unannounced standardized patient (SP) encounters at baseline. Intervention physicians received SP verbal feedback; academic detailing to review cancer screening guidelines, red flags for identifying low HL, and strategies for effective counseling; and web-based tutorial of SP comments and checklist items hyperlinked to reference articles/websites.

MAIN MEASURES

Baseline PCP self-rated proficiency, SP ratings of physician general cancer risk communication and SDM skills, patient perceived involvement in care.

RESULTS

Baseline assessments show physicians rated their proficiency in discussing cancer risks and eliciting patient preference for treatment/decision-making as “very good”. SPs rated physician exploration of perceived cancer susceptibility, screening barriers/motivators, checking understanding, explaining screening options and associated risks/benefits, and eliciting preferences for screening as “satisfactory”. Clinic patients rated their doctor’s facilitation of involvement in care and information exchange as “good”. However, they rated their participation in decision-making as “poor”.

DISCUSSION

The baseline skills assessment suggests a need for physician training in cancer risk communication and shared decision making for patients with low HL. We are determining the effectiveness of teaching methods, required resources and long-term feasibility for a CME program.

     

Extrahepatic Malignancies in Primary Biliary Cholangitis

Purpose of Review

The association between extrahepatic malignancy and primary biliary cholangitis (PBC) has been studied only partially. The goal of this paper is to update this topic, reviewing the most recent literature.

Recent Findings

Studies comparing the incidence of cancer with the general population and meta-analysis studies failed to find a specific association between extrahepatic malignancy (including breast cancer, gastrointestinal cancers, reproductive tumors, and myeloproliferative diseases) and PBC. Moreover, it has been found that the development of cancer does not influence the natural history of the disease. The risk factors associated with cancer development are advanced histological stage and extrahepatic autoimmunity.

Summary

Cancer screening programs for PBC patients are not needed other than those already present for the general population. However, more high-quality case-control studies on the stratification of risk for extrahepatic cancers in PBC are warranted in the future.

     

Trends in Frequency and Management of Obstructing Colorectal Cancers in a Well-Defined Population

Background

Few population-based studies investigate obstructing colorectal cancers. This study was designed to describe trends in their frequency and management.

Methods

Data were obtained for 13,331 colorectal cancers registered by the population-based cancer registry of Burgundy, France, between the years 1976 and 2000.

Results

Obstructing cancers represented 8.3 percent of all colorectal cancers. This proportion was stable throughout the study. Resection for cure increased from 54.9 percent (1976–1980) to 71.4 percent (1996–2000; P?=?0.011). Using multivariate analysis, site of cancer and period of diagnosis were the only factors significantly associated to a curative resection. Postoperative mortality for obstructing colorectal cancers decreased from 32.6 percent (1976–80) to 15.2 percent (1996–2000; P?

Conclusion

The frequency of obstructing colorectal cancers has remained unchanged for 25 years. Operative mortality is still high, although some improvements have occurred. Efforts must be made to diagnose colorectal cancers before obstruction occurs. Mass screening represents a promising approach.

     

Clinical characteristics and management of gastric tube cancer after esophagectomy

Background

Gastric cancer is the second most common malignancy, overlapping with thoracic esophageal cancer (TEC). Among them, metachronous gastric tube cancers after TEC surgery have been increasing. The aims of this study were to examine the clinicopathological factors and treatment outcomes of gastric tube cancer (GTC) after TEC surgery.

Methods

Thirty-three GTCs in 30 cases after TEC treated between 1997 and 2016 were investigated retrospectively.

Results

Most cases were males. The median interval from TEC surgery to GTC occurrence was 57 (6.5–107.5) months. Almost 2/3 lesions occurred in the lower third of the gastric tube (21/33); 29 lesions (in 26 cases) were superficial cancers, and 4 lesions were advanced cancers. Twenty-two lesions of superficial cancer were differentiated type, and the remaining seven lesions were undifferentiated type. Treatment for superficial cancer had previously been performed with partial gastric tube resection (10 lesions), and the number of cases undergoing endoscopic submucosal dissection (ESD) had increased recently (19 lesions). Most cases with superficial cancer survived without relapse. Four lesions of advanced cancer were found after a relatively long interval following TEC surgery. Most lesions of advanced cancer were scirrhous, undifferentiated type, and they died due to GTC.

Conclusion

GTCs may occur late in the postoperative course following TEC surgery. If they are discovered at an early stage, these lesions can be cured with ESD. Long-term periodic endoscopic examinations after TEC surgery are important.

     

Seltene thorakale Tumorentitäten

Background

Rare forms of cancer account for 22?% of all cancers and 21?% of thoracic cancers in the European Union (EU). The incidence, defined as < 6 new cases per 100,000 per year appears to be more useful to represent the frequency of rare cancers than the prevalence. Due to this rarity, evidence-based concepts for the diagnostic work-up, therapy and follow-up are still lacking. The aim of this study was to identify and to review the epidemiology and clinical manifestation of selected rare thoracic tumor entities.

Material and methods

With the help of international tumor registries (e.?g. RareCareNet and Rare Cancer Network) rare tumor entities originating from the lungs, pleura and thymus were identified and reviewed.

Results

The focus was on the following entities: idiopathic pulmonary neuroendocrine cell hyperplasia, adenoid cystic carcinoma, congenital peribronchial myofibroblastic tumor, primary pulmonary melanoma, localized malignant mesothelioma and thymic carcinoma. Approximately 75?% of all rare cancers had an incidence of < 0.5 cases per 100,000 per year. The relative 5-year survival for rare tumors was reduced due to a significant latency period in diagnosis, to a lack of evidence-based guidelines and to high mortality.

Conclusion

Rare thoracic cancers should be treated in multidisciplinary centers for thoracic oncology and surveillance by internationally cooperating cancer registries. The European RareCareNet collects and analyzes patient data from 94 cancer registries in 24 EU countries.

     

Strukturierte onkologische Nachsorge

Background

Patients with cancer and recommendations for aftercare are increasing worldwide.

Objectives

Presentation of the current follow-up guidelines of selected gastrointestinal tumors.

Materials and methods

The current German S3 guidelines for colorectal cancer, pancreatic cancer, hepatocellular carcinoma, and gastric cancer are analyzed.

Results

The S3 guidelines for colorectal cancer and hepatocellular carcinoma favor structured aftercare. For a period of 2–5 years, a combination of case history, physical examination, imaging, endoscopy, and determination of tumor markers is recommended. Advocacy for structured aftercare for pancreatic or gastric cancer must be decided individually. In general, the follow-up time and interval should be adjusted to the complaints of the patient, regardless of the tumor type.

Conclusions

Structured aftercare makes sense and is already part in the monitoring of selected gastrointestinal tumors.

     

Selection of EMR and ESD for Laterally Spreading Lesions of the Colon

Introduction

Colonic laterally spreading lesions (LSL) are increasingly managed using endoscopic methods that comprise two main techniques: endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD).

Purpose of Review

In this review, we aimed to review the most recent literature on selection of the best endoscopic technique in the management of colonic LSL.

Recent Findings

EMR and ESD are complimentary techniques in the management of patients with colonic LSL.

Summary

EMR is safe and effective in most patients with LSL, except for cancers with submucosal invasion in whom R0 resection is favored.

     

The clinicopathological significance of heat shock protein 70 and glutamine synthetase expression in hepatocellular carcinoma

Background/purpose

Heat shock protein 70 (HSP70) and glutamine synthetase (GS) have been proposed to be promising markers for the differentiation of malignant and benign hepatocellular lesions. The aim of this study was to investigate the clinicopathological significance of the expression of HSP70 and GS in surgically resected hepatocellular carcinoma (HCC).

Methods

The authors collected 412 HCC samples and 120 non-neoplastic hepatic tissue samples and performed an immunohistochemical study.

Results

HSP70 staining was observed in 282 of 392 HCC samples (71.9%), and GS immunoreactivity was observed in 212 of 395 HCC cases (53.7%). Of the several clinicopathological parameters examined, microscopic vascular invasion, a large tumor size, and a high Edmonson–Steiner grade were found to be correlated with positive staining for HSP70 (P = 0.032, 0.002, and 0.012, respectively). Survival analysis showed a correlation between HSP70 expression and disease-free survival. GS was not found to be related to clinicopathological parameters.

Conclusions

The findings of the present study suggest that HSP70 be viewed as a predictor of prognosis as well as a useful diagnostic marker for HCC.

     

The Validity of HCC Diagnosis Codes in Chronic Hepatitis B Patients in the Veterans Health Administration

Background

Administrative databases that include diagnostic codes are valuable sources of information for research purposes.

Aim

To validate diagnostic codes for hepatocellular carcinoma (HCC) in chronic hepatitis B patients.

Methods

We conducted a retrospective study of patients with chronic HBV seen in the national Veterans Administration (VA). HCC cases were identified by the presence of ICD-9 code 155.0. We randomly selected 200 HBV controls without this code as controls. We manually reviewed the electronic medical record (EMR) of all cases and controls to determine HCC status. We calculated the positive predictive value (PPV), negative predictive value (NPV), sensitivity, and specificity for the HCC code. We conducted an implicit review of the false-positive cases to determine possible reasons for the miscoding.

Results

Of the 8350 patients with HBV, 416 had an ICD-9 code for HCC. Of these 416, 332 patients had confirmed HCC and 61 did not; HCC status was indeterminate for 23 patients. Of the 200 controls, none had HCC confirmed in the EMR. The PPV ranged from 85.3 to 80.0% and specificity ranged from 99.2 to 99.0% based on classification of indeterminate cases as true versus false positives, respectively. The NPV, sensitivity, and specificity were 100%. Two-thirds of false-positive cases were diagnosed with HCC prematurely as a workup of liver mass and latter imaging and/or biopsy were not diagnostic for HCC.

Conclusion

The diagnostic code of HCC in chronic HBV patients in the VHA data is predictive of the presence of HCC in medical records and can be used for epidemiological and clinical research.

     

MicroRNA-98 Suppress Warburg Effect by Targeting HK2 in Colon Cancer Cells

Background

Warburg effect is a hallmark of cancer cells. Accumulating evidence suggests that microRNAs (miRs) could regulate such metabolic reprograming. Aberrant expression of miR-98 has been observed in many types of cancers. However, its functions and significance in colon cancer remain largely elusive.

Aims

To investigate miR-98 expression and the biological functions in colon cancer progression.

Methods

miR-98 expression levels were determined by quantitative RT-PCR in 215 cases of colon cancer samples. miR-98 mimic or inhibitor was used to test the biological functions in SW480 and HCT116 cells, followed by cell proliferation assay, lactate production, glucose uptake, and cellular ATP levels assay and extracellular acidification rates measurement. Western blot and luciferase assay were used to identify the target of miR-98.

Results

miR-98 was significantly down-regulated in colon cancer tissues compared to adjacent colon tissues and acted as a suppressor for Warburg effect in cancer cells. miR-98 inhibited glycolysis by directly targeting hexokinase 2, or HK2, illustrating a novel pathway to mediate Warburg effect of cancer cells. In vitro experiments further indicated that HK2 was involved in miR-98-mediated suppression of glucose uptake, lactate production, and cell proliferation. In addition, we detected HK2 expression in colon cancer tissues and found that the expressions of miR-98 and HK2 were negatively correlated.

Conclusion

miR-98 acts as tumor suppressor gene and inhibits Warburg effect in colon cancer cells, which provided potential targets for clinical treatments.

     

Re-evaluation of lipiodolized transarterial chemoembolization therapy for intrahepatic recurrence of hepatocellular carcinoma after curative liver resection

Background/Purpose

While lipiodolized transarterial chemoembolization (lip-TACE) is effective for treating unresectable hepatocellular carcinoma (HCC), its effect for treating recurrent HCC after curative liver resection needs to be clarified.

Methods

Of 163 patients who had undergone curative liver resection between 1992 and December 2003, 65 patients (39.8%) had recurrent HCC in the liver without extrahepatic recurrence and were indicated for lip-TACE. The overall survival rate after lip-TACE was calculated, and its correlation with factors such as the histology of the primary HCC and background noncancerous tissue were analyzed.

Results

The overall survival rates after lip-TACE after the detection of the first recurrent HCC were 82.6%, 44.5%, and 24.8% at 1, 3, and 5 years, respectively. The factors affecting patient survival after lip-TACE were microscopic portal venous involvement of HCC at liver resection, grade of inflammation in the noncancerous liver parenchyma, and recurrence within 1 year after the initial liver resection. Multivariate analysis showed that the period between the resection and first recurrence had the highest hazard ratio.

Conclusions

Lip-TACE is a reasonable procedure for treating recurrent HCC in selected patients who are not eligible for hepatic re-resection. When HCC recurred within 1 year from the primary liver resection, the effect of lip-TACE on patient survival was limited.