The clinical value of PERCIST to predict tumour response and prognosis of patients with oesophageal cancer treated by neoadjuvant chemoradiotherapy.

AIM: To examine whether Positron Emission Tomography Response Criteria in Solid Tumours (PERCIST) is useful to predict tumour response and prognosis of patients with oesophageal cancer who received neoadjuvant chemoradiotherapy (NACRT) followed by surgery. MATERIALS AND METHODS: This multicentre retrospective study included 60 patients with oesophageal cancer who underwent 2-[18F]-fluoro-2-deoxy-d-glucose positron-emission tomography/computed tomography (18F-FDG-PET/CT) before and after NACRT prior to surgery from January 2007 and June 2016. The correlation between pathological response and PERCIST was assessed by χ2 test. The prognostic significance was assessed by the Kaplan-Meier method and Cox regression analysis. RESULTS: There were 30 responders and 30 non-responders pathologically. The complete metabolic response (CMR), partial metabolic response (PMR), stable metabolic disease (SMD), and progressive metabolic disease (PMD) were seen in 22, 29, seven, and two patients, respectively. There was a significant correlation between pathological response and PERCIST (p<0.001). Forty patients showed eventual progression, and 20 patients were alive without progression between the start of NACRT and last clinical follow-up (median follow-up period; 27 months [range, 3-107]). Pathological stage and PERCIST were significant for progression-free survival (PFS; p=0.044 and 0.006, respectively) and also significant for overall survival (OS; p=0.009 and 0.001, respectively) at univariate analysis. Pathological lymph node staging was also significant for OS at univariate analysis (p=0.018). At multivariate analysis, PERCIST remained significant and independent for PFS (hazard ratio [HR]: 1.59, p=0.046) and OS (HR: 1.82, p=0.008). CONCLUSION: PERCIST may be useful for predicting tumour response and prognosis of patients with oesophageal cancer who received NACRT.

Current status of integrating oncology and palliative care in Japan: a nationwide survey.

BACKGROUND: Palliative care (PC) is increasingly recognized as essential for oncology care, and several academic societies strongly recommend integrating oncology and palliative care (IOP) in daily practice. Similarly, the Japanese government encouraged the implementation of IOP through the Cancer Control Act of 2007; however, its detailed progress remains unclear. Therefore, this cross-sectional nationwide survey was conducted to investigate the current status and hospital executive physicians' perception of IOP. METHODS: The questionnaire was developed based on IOP indicators with international consensus. It was distributed to executive physicians at all government-designated cancer hospitals (DCHs, n = 399) and matched non-DCHs (n = 478) in November 2017 and the results were compared. RESULTS: In total, 269 (67.4%) DCHs and 259 (54.2%) non-DCHs responded. The number of PC resources in DCHs was significantly higher than those in non-DCHs (e.g., full-time PC physicians and nurses, 52.8% vs. 14.0%, p < 0.001; availability of outpatient PC service ≥3 days per week, 47.6% vs. 20.7%, p < 0.001). Routine symptom screening was more frequently performed in DCHs than in non-DCHs (65.1% vs. 34.7%, p < 0.001). Automatic trigger for PC referral availability was limited (e.g., referral using time trigger, 14.9% vs. 15.3%, p = 0.700). Education and research opportunities were seriously limited in both types of hospitals. Most executive physicians regarded IOP as beneficial for their patients (95.9% vs. 94.7%, p = 0.163) and were willing to facilitate an early referral to PC services (54.7% vs. 60.0%, p < 0.569); however, the majority faced challenges to increase the number of full-time PC staff, and < 30% were planning to increase the staff members. CONCLUSIONS: This survey highlighted a considerable number of IOP indicators met, particularly in DCHs probably due to the government policy. Further efforts are needed to address the serious research/educational gaps.

New physician specialty training system impact on distribution of trainees in Japan.

OBJECTIVES: The problem of uneven distribution of medical services and inequitable distribution of physicians is drawing much attention worldwide. Revealing how changes in the specialty training system in Japan have affected the distribution of doctors could help us understand this problem. In 2018, a new and standardized specialty training system was implemented by the Japanese Medical Specialty Board, which is recognized by the Ministry of Health, Labor and Welfare. The purpose of this study was to investigate how this new system has affected the geographical distribution of doctors commencing specialty training (trainees) and choice of specialty in Japan. STUDY DESIGN: Retrospective observational study. METHODS: The change in the number of trainees between the control period (2012-2014) and 2018 was investigated, taking into account the prefecture and specialty selected. Population, the proportion of residents aged 65 years or older (aging rate), and the total number of overall doctors in each prefecture were considered as the background characteristics of each prefecture. We created a Lorenz curve and calculated the Gini coefficient for the distribution of trainees. RESULTS: In 2018, the number of trainees per 100,000 population increased to 6.6 nationwide compared with 5.5 during the control period. The number of trainees per 100,000 population in 2018 increased in prefectures with a large population of ≧ 2,000,000, a low aging rate (<27%), and a high doctor density (≧ 250 doctors per 100,000 population). The Gini coefficient showed an increase to 0.226 in 2018 compared with only 0.160 during the control period. CONCLUSIONS: After the implementation of the new training system, there was an increase in the number of doctors enrolling in specialty programs, and the specialties other than internal medicine and surgery have attracted more trainees. Inequality in the distribution of doctors between urban and rural prefectures worsened. This indicates the need to explore new ways of balancing distribution while maintaining optimal opportunities for specialist training.

Effective countermeasures for Salmonella contamination in actual oilmeal-manufacturing plant in India.

AIMS: Salmonella contamination in the manufacturing process of an overseas oilmeal plant was investigated and countermeasures for Salmonella contamination were evaluated. METHODS AND RESULTS: Salmonella was detected from deposits and adhered materials inside the main processing equipment. Specifically high contamination was observed in the equipment associated with the meal cooler, with several Salmonella serovars being detected. A number of Salmonella serovars were also detected in the equipment of the fine powder recovery process. To prevent Salmonella contamination of oilmeal products, effective countermeasures that have been employed in Japan were implemented. By removing residues from the equipment and disinfecting the interior of the equipment, a significant decrease in the contamination rate of oilmeal products was achieved compared to before sanitation (P < 0·05). CONCLUSIONS: Effective countermeasures to control Salmonella contamination in the overseas manufacturing process of oilmeal were established. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first report focusing on Salmonella countermeasures in an actual oilmeal-manufacturing plant overseas.

Palliative sedation in clinical scenarios: results of a modified Delphi study.

PURPOSE: To explore the consistency in international expert opinions about palliative sedation. METHODS: A modified electronic-Delphi procedure was carried out in two rounds. On hundred nine eligible experts were identified from their publications in MEDLINE related with terminal delirium, dyspnea and palliative sedation in the last 3 years. Delphi study included three vignettes of cancer patients and two non-cancer patients, with an estimated survival of days and severe suffering secondary to refractory complications. Experts were asked about whether they would perform continuous sedation and sedation level (described as Richmond Agitation Sedation Scale or defined as patient/family report of symptom relief). Consensus was considered when 70% or more of the experts agreed on a certain topic. RESULTS: Thirty-four and 27 panellists completed the 2 Delphi rounds, respectively. Participants were from the USA, Canada, Europe, Australia and Asia. One hundred per cent, 97% and 88% of the respondent agreed use of sedatives, continuously or temporary, in cases of refractory delirium, dyspnea secondary to lung cancer and GOLD IV-EPOC. There were discrepancies for cases of dementia and psycho-existential suffering. Expert selection of continuous palliative sedation was 93% for delirium, 41% for cancer dyspnea, 66% for EPOC dyspnea, 22% for agitation/pain in dementia and 19% for existential suffering. Responses about types and levels of sedation did not achieve consensus in any cases. CONCLUSIONS: The Delphi study failed to reach consensus in continuous palliative sedation and sedation levels for patients with refractory symptoms described in hypothetical clinical scenarios.

Trend in unequal geographical distribution of dentists by age and gender in Japan from 1996-2014.

OBJECTIVES: To evaluate the relationship between dentists' demographic changes and their uneven geographical distribution. METHODS: Secondary analysis of nationwide government surveys, to assess trends in the geographical distribution of dentists by gender and age from 1996 to 2014 in Japan. RESULTS: The Gini-coefficient for the number of dentists per population from 47 prefectures decreased from 0.084 in 1996 to 0.069 in 2014. The coefficients for female (0.124-0.144) were higher than for male dentists (0.058-0.081). Coefficients for dentists aged 60 and older were lower than those for dentists younger than 40 in 2014 (male: 0.060 vs. 0.112; female: 0.107 vs. 0.169). CONCLUSION: The geographical maldistribution of dentists in Japan has improved. Demographic changes among dentists, including the increasing number of female dentists, could moderate this improvement.

Trend in unequal geographical distribution of doctors by age and sex in Japan from 2004 to 2014.

OBJECTIVES: In Japan, the proportion of female doctors and elderly doctors is increasing as in other countries. We investigated the relationship between doctors' demographic changes and their geographical distribution. STUDY DESIGN: A national database study. METHODS: We assessed trends in unequal geographical distribution of the number of doctors by sex and age from 2004 to 2014 in Japan. RESULTS: The Gini coefficient values for the number of female doctors (0.18) were larger than those for male doctors across all generations (0.13-0.14). The Gini coefficient values for the number of elderly doctors aged 60 years and older (male: 0.12, female: 0.18-0.23) were larger than those for majority age groups aged 40-59 years (male: 0.10, female: 0.16-0.17). CONCLUSION: The persisting geographical maldistribution of doctors may be associated with demographic changes, such as increase in the number of female doctors.

Transition from Collisional to Collisionless Regimes in Interpenetrating Plasma Flows on the National Ignition Facility.

A study of the transition from collisional to collisionless plasma flows has been carried out at the National Ignition Facility using high Mach number (M>4) counterstreaming plasmas. In these experiments, CD-CD and CD-CH planar foils separated by 6-10 mm are irradiated with laser energies of 250 kJ per foil, generating ∼1000 km/s plasma flows. Varying the foil separation distance scales the ion density and average bulk velocity and, therefore, the ion-ion Coulomb mean free path, at the interaction region at the midplane. The characteristics of the flow interaction have been inferred from the neutrons and protons generated by deuteron-deuteron interactions and by x-ray emission from the hot, interpenetrating, and interacting plasmas. A localized burst of neutrons and bright x-ray emission near the midpoint of the counterstreaming flows was observed, suggesting strong heating and the initial stages of shock formation. As the separation of the CD-CH foils increases we observe enhanced neutron production compared to particle-in-cell simulations that include Coulomb collisions, but do not include collective collisionless plasma instabilities. The observed plasma heating and enhanced neutron production is consistent with the initial stages of collisionless shock formation, mediated by the Weibel filamentation instability.

Pathogenesis of Renal Lesions in Chickens After Experimental Infection With 9a5b Newcastle Disease Virus Mutant Isolate.

In this study, we investigated the pathogenesis of Newcastle disease virus (NDV) in the chicken kidney. Twenty-six 32-day-old specific pathogen-free chickens were intranasally inoculated with the 9a5b NDV mutant isolate. Kidney tissue samples, collected at 6 and 12 hours postinoculation (hpi) and 1, 2, 3, 5, and 10 days postinoculation (dpi), were analyzed by histopathology, immunohistochemistry (IHC), reverse transcription polymerase chain reaction (RT-PCR), and virus titration. Histopathologically, tubulointerstitial nephritis was detected in the renal cortex and predominantly in the medulla. Nephrotropism of 9a5b NDV was confirmed by IHC, RT-PCR, and virus isolation. Massive degenerative changes and infiltration of CD3-immunopositive cells accompanied replication of the 9a5b NDV isolate in chicken kidneys. In conclusion, pathological changes that were caused by NDV in chicken kidneys were similar to those caused by avian influenza virus, infectious bronchitis virus, and avian nephritis virus, and this highlights the importance of including NDV in the differential diagnosis of kidney disease in chickens.

Indicators of integration of oncology and palliative care programs: an international consensus.

BACKGROUND: Recently, the concept of integrating oncology and palliative care has gained wide professional and scientific support; however, a global consensus on what constitutes integration is unavailable. We conducted a Delphi Survey to develop a consensus list of indicators on integration of specialty palliative care and oncology programs for advanced cancer patients in hospitals with ≥100 beds. METHODS: International experts on integration rated a list of indicators on integration over three iterative rounds under five categories: clinical structure, processes, outcomes, education, and research. Consensus was defined a priori by an agreement of ≥70%. Major criteria (i.e. most relevant and important indicators) were subsequently identified. RESULTS: Among 47 experts surveyed, 46 (98%), 45 (96%), and 45 (96%) responded over the three rounds. Nineteen (40%) were female, 24 (51%) were from North America, and 14 (30%) were from Europe. Sixteen (34%), 7 (15%), and 25 (53%) practiced palliative care, oncology, and both specialties, respectively. After three rounds of deliberation, the panelists reached consensus on 13 major and 30 minor indicators. Major indicators included two related to structure (consensus 95%-98%), four on processes (88%-98%), three on outcomes (88%-91%), and four on education (93%-100%). The major indicators were considered to be clearly stated (9.8/10), objective (9.4/10), amenable to accurate coding (9.5/10), and applicable to their own countries (9.4/10). CONCLUSIONS: Our international experts reached broad consensus on a list of indicators of integration, which may be used to identify centers with a high level of integration, and facilitate benchmarking, quality improvement, and research.

Randomized phase III trial of treatment duration for oral uracil and tegafur plus leucovorin as adjuvant chemotherapy for patients with stage IIB/III colon cancer: final results of JFMC33-0502.

BACKGROUND: While adjuvant chemotherapy is preferable for high-risk colon cancer, treatment duration is controversial. Oral uracil and tegafur (UFT)/leucovorin (LV) is widely used as a standard adjuvant chemotherapy for colon cancer in Japan. We conducted a phase III trial to investigate the optimal duration of adjuvant chemotherapy for stage IIB/III colon cancer. PATIENTS AND METHODS: Patients with curatively resected stage IIB/III colon cancer were eligible for enrollment in this trial. Patients were registered within 6 weeks after surgery and were randomly assigned to receive UFT/LV for 28 of 35 days for 6 months in the control group or for 5 consecutive days per week for 18 months in the study group. The primary end point was the disease-free survival (DFS), and the secondary end points were overall survival (OS) and safety. RESULT: A total of 1071 patients were registered from 233 centers. A statistically significant difference in DFS was not observed between the study group and the control group; the 5-year DFS was 69% in the study group and 69% in the control group. The 5-year OS was 85% in the study group and 85% in the control group. CONCLUSION: Eighteen-month treatment with UFT/LV did not improve DFS or OS compared with 6-month UFT/LV treatment in patients with stage IIB/III colon cancer. The important finding from this study is that not 18 months but 6 months of treatment is enough for postoperative UFT/LV for stage IIB/III colon cancer. CLINICAL TRIAL NUMBER: UMIN-CTR C000000245.

Lifestyle risk factors for pressure ulcers in community-based patients with spinal cord injuries in Japan.

STUDY DESIGN: Case-control study. OBJECTIVES: To identify daily living-related risk factors for pressure ulcer (PU) occurrence in community-living patients with spinal cord injury (SCI). To determine whether seat pressure influences PU occurrence, and how often patients with SCI perform pressure relief activities while living in the community. SETTING: Kanagawa Rehabilitation Hospital, Kanagawa, Japan. METHODS: Thirty-one patients admitted to this hospital for PU treatment were included in the case (PU) group. Thirty outpatients who did not have PUs at the time of the study, and had lived without PUs for at least a year, were included in the control (No PU) group. Patients were interviewed about lifestyle-related PU risk factors and a pressure-mapping system was used to measure interface pressure (IP) on their wheelchair seat. The No PU group patients recorded their daily activities and pressure relief maneuvers for 1 week. RESULTS: Eight lifestyle factors and one risk assessment scale significantly differed between groups. Three factors showed significant odds ratios by logistic regression. IP did not significantly differ between groups. The self-counted number of pressure relief maneuvers (median (25th-75th percentile)) performed per hour in the No PU group was 2.5 (0.7-4.3) and including transfer and urination was 3.5 (2.0-5.3). CONCLUSION: We identified potential PU risk factors related to lifestyle. The scores of one risk assessment scale were also associated with PU risk. Our results did not suggest an IP damage threshold. Patients in the No PU group performed pressure relief maneuvers, including related activities, approximately once every 17 min.

Peripheral circulation evaluation with near-infrared spectroscopy in skeletal muscle during cardiopulmonary bypass.

BACKGROUND: We designed a non-invasive, observational, real-time study, using near-infrared spectroscopy (NIRS) to assess the in vivo effects of cardiopulmonary bypass (CPB) on patients' skeletal muscle as well as the effects of hemodilution and hypothermia on tissue oxygen delivery during CPB. METHODS: The study included 20 consecutive adult patients undergoing open-heart surgery with CPB. Evaluation parameters for peripheral circulation were measured using the NIRO-200NX and recorded every 30 seconds. To assess how hemodilution influences peripheral circulation parameters, we compared data between a group of patients with hematocrit (Hct) values >22% (high Hct group) and those with Hct values ⩽22% (low Hct group). RESULTS: Changes in the concentration of oxygenated hemoglobin (ΔO2Hb, µmol/L), which flows into the skeletal muscle, was an important factor for deciding the tissue oxygenation index (TOI%), showing the tissue oxygen saturation. The low Hct group showed a significant increase in the normalized tissue hemoglobin index (nTHI), showing the percentage change in the amount of initial hemoglobin and TOI compared to the high Hct group. Changes in the concentration of oxygenated hemoglobin (ΔO2Hb, µmol/L) and deoxygenated hemoglobin (ΔHHb, µmol/L) were significantly less in the low Hct group than in the high Hct group, thus, showing good peripheral circulation despite the low hematocrit levels. CONCLUSION: Our study indicated the presence of a compensatory mechanism in which increased blood flow of the microcirculation is in compensation for the lack of oxyhemoglobin delivery caused by hemodilution.

Favourable swallowing outcomes after subtotal glossectomy with laryngeal suspension.

Subtotal or total glossectomy for advanced tongue cancer has an adverse impact on swallowing. The purpose of this retrospective study was to analyse postoperative swallowing outcomes and to determine the ideal reconstruction method in these patients. The clinical and swallowing data of patients with tongue cancer who underwent subtotal glossectomy at the study institution between 2005 and 2019 were reviewed retrospectively. Data were available for 101 patients. The most common reconstruction method was a free rectus abdominis musculocutaneous flap (69 cases). The postoperative feeding tube dependency rate was 11.1% at discharge and 9.4% at 1 year. During the study period, laryngeal suspension and/or a cricopharyngeal myotomy was performed in 39 patients (38.6%), with 25 of these operations performed after 2017. Patients treated in 2017-2019 were significantly more able to take thin liquid (P < 0.001) and lost less weight (P = 0.015) compared to those treated in 2005-2016. Multivariate analysis of 61 patients who did not undergo laryngeal suspension and/or cricopharyngeal myotomy showed significant feeding tube dependency in those aged 65 years and older (P = 0.004). Thin liquid intake was significantly improved after subtotal glossectomy with laryngeal suspension, which led to better postoperative swallowing and improved quality of life.

Interventricular inflow time difference assessed by dual pulsed-wave Doppler echocardiography in dogs with myxomatous mitral valve disease.

INTRODUCTION: Interventricular inflow time difference (IVID), which is defined as the time interval between the opening of the mitral valve and the opening of the tricuspid valve, hold prognostic value in human patients with heart failure. Few reports regarding IVID are available in dogs. ANIMALS: Ninety dogs with myxomatous mitral valve disease (MMVD) and 47 dogs without heart disease. Dogs with MMVD received unstandardized therapy based on the stage of disease. MATERIALS AND METHODS: This was a prospective cohort study. Dogs were classified into two groups based on IVID: tricuspid opening preceding mitral opening (TOP) and mitral opening preceding tricuspid opening (MOP). The potential influence of the MOP group at enrollment on the primary outcome (cardiac-related death) was determined by Kaplan-Meier analysis. RESULTS: Almost all dogs without heart disease (97.9%) were classified in the TOP group. Twenty-nine dogs (32.2%) were classified in the MOP group. Left heart size, transmitral early diastolic inflow velocity, and right ventricular Tei index were significantly greater in the MOP group compared to those in the TOP group. Cardiac-related death were observed in 34 dogs (40.5%). The dogs in the MOP group at initial examination had shorter survival times than those in the TOP group (586 days vs. >1,831 days; 95% confidence interval, 237-714 days vs. 1,037 days to >1,831 days; P<0.001). CONCLUSIONS: Interventricular inflow time difference is potentially useful for prognostic assessments in dogs with MMVD. Further prospective studies that quantify the repeatability and influence of therapy on IVID are needed.

Comparative study on the pathogenesis of the generated 9a5b Newcastle disease virus mutant isolate between chickens and waterfowl.

Lentogenic Newcastle disease viruses (NDVs), circulating among waterfowl, have the potential to become highly pathogenic by replication in chickens. The pathological studies that compare NDV infections in chickens and waterfowl are rare. The virulent 9a5b mutant NDV isolate was generated by passaging the lentogenic Goose/Alaska/415/91 NDV isolate in chickens. The pathogenesis of the virulent 9a5b mutant isolate is unknown in both chickens and waterfowl. In this study, the virulent 9a5b mutant NDV isolate was inoculated intranasally in 32-day-old specific pathogen-free white Leghorn chickens and Japanese commercial ducks. Unlike ducks, which remained clinically normal throughout the study, chickens had depression, gasping, oral discharges, and greenish-white soft feces. Gross and histologic lesion patterns as well as viral replication supported the differing clinical outcome. Ducks had slight inflammation mainly in respiratory and digestive tracts, whereas slight nonpurulent encephalitis, necrotizing pancreatitis, tubulointerstitial nephritis, and mild inflammation in respiratory and digestive tracts were detected in chickens. In agreement, interferon-beta (IFN-ß)-immunopositive signals were more intense in lung tissue of ducks than that of chickens, and NDV replications were detected intensively in chicken tissues. These results suggest that the 9a5b mutant NDV isolate is more virulent in chickens, and slight histological lesions were induced in ducks even with virulent NDVs.

Germ cell transplantation as a potential biotechnological approach to fish reproduction.

Although the use of germ cell transplantation has been relatively well established in mammals, the technique has only been adapted for use in fish after entering the 2000s. During the last decade, several different approaches have been developed for germ cell transplantation in fish using recipients of various ages and life stages, such as blastula-stage embryos, newly hatched larvae and sexually mature specimens. As germ cells can develop into live organisms through maturation and fertilization processes, germ cell transplantation in fish has opened up new avenues of research in reproductive biotechnology and aquaculture. For instance, the use of xenotransplantation in fish has lead to advances in the conservation of endangered species and the production of commercially valuable fish using surrogated recipients. Further, this could also facilitate the engineering of transgenic fish. However, as is the case with mammals, knowledge regarding the basic biology and physiology of germline stem cells in fish remains incomplete, imposing a considerable limitation on the application of germ cell transplantation in fish. Furthering our understanding of germline stem cells would contribute significantly to advances regarding germ cell transplantation in fish.

Prognostic value of left atrial stiffness estimated using echocardiography in dogs with myxomatous mitral valve disease.

INTRODUCTION: No studies have investigated the prognostic value of left atrial stiffness (LASt) estimated using echocardiography in dogs with myxomatous mitral valve disease (MMVD). ANIMALS: Seventy-two dogs had MMVD and 46 dogs were healthy dogs. MATERIALS AND METHODS: Clinical retrospective cohort study. The survival information of MMVD dogs that underwent echocardiographic examination was obtained. The peak velocities of early diastolic transmitral flow (E) and mitral annular motion as determined by pulsed wave Doppler (E') were determined. The left atrial reservoir strain (εS) was determined by two-dimensional speckle tracking echocardiography of the left atrium. The LASt was estimated by the formula: E/E'/εS. The 95% prediction interval of LASt was computed from the data of the healthy dogs. RESULTS: Seventeen dogs having MMVD died of cardiac-related causes with 55 MMVD dogs censored. The MMVD dogs with LASt > its 95% upper prediction limit (LASt > 0.56; n = 26; median survival time, 484 days; 95% confidence interval, 283 days-indeterminable) had shorter survival times (P<0.001) than those with LASt ≤ its 95% upper prediction limit (LASt ≤ 0.56; n = 46; median survival time, >1112 days; 95% confidence interval, indeterminable). Multivariable Cox's proportional hazard analysis demonstrated that the ratio of the left atrial dimension to the aortic annulus dimension and LASt were independent predictors of cardiac-related death among conventional echocardiographic indices, εS and LASt in MMVD dogs. CONCLUSIONS: In dogs with MMVD, increased LASt estimated using echocardiography is an independent predictor of cardiac-related death, and LASt can be more useful for prognostication than εS.

Glycogen synthase 1 targeting reveals a metabolic vulnerability in triple-negative breast cancer.

BACKGROUND: Hypoxia-induced glycogen turnover is implicated in cancer proliferation and therapy resistance. Triple-negative breast cancers (TNBCs), characterized by a hypoxic tumor microenvironment, respond poorly to therapy. We studied the expression of glycogen synthase 1 (GYS1), the key regulator of glycogenesis, and other glycogen-related enzymes in primary tumors of patients with breast cancer and evaluated the impact of GYS1 downregulation in preclinical models. METHODS: mRNA expression of GYS1 and other glycogen-related enzymes in primary breast tumors and the correlation with patient survival were studied in the METABRIC dataset (n = 1904). Immunohistochemical staining of GYS1 and glycogen was performed on a tissue microarray of primary breast cancers (n = 337). In four breast cancer cell lines and a mouse xenograft model of triple-negative breast cancer, GYS1 was downregulated using small-interfering or stably expressed short-hairpin RNAs to study the effect of downregulation on breast cancer cell proliferation, glycogen content and sensitivity to various metabolically targeted drugs. RESULTS: High GYS1 mRNA expression was associated with poor patient overall survival (HR 1.20, P = 0.009), especially in the TNBC subgroup (HR 1.52, P = 0.014). Immunohistochemical GYS1 expression in primary breast tumors was highest in TNBCs (median H-score 80, IQR 53-121) and other Ki67-high tumors (median H-score 85, IQR 57-124) (P < 0.0001). Knockdown of GYS1 impaired proliferation of breast cancer cells, depleted glycogen stores and delayed growth of MDA-MB-231 xenografts. Knockdown of GYS1 made breast cancer cells more vulnerable to inhibition of mitochondrial proteostasis. CONCLUSIONS: Our findings highlight GYS1 as potential therapeutic target in breast cancer, especially in TNBC and other highly proliferative subsets.

Kelvin-Helmholtz turbulence associated with collisionless shocks in laser produced plasmas.

We report the experimental results of a turbulent electric field driven by Kelvin-Helmholtz instability associated with laser produced collisionless shock waves. By irradiating an aluminum double plane target with a high-power laser, counterstreaming plasma flows are generated. As the consequence of the two plasma interactions, two shock waves and the contact surface are excited. The shock electric field and transverse modulation of the contact surface are observed by proton radiography. Performing hydrodynamic simulations, we reproduce the time evolutions of the reverse shocks and the transverse modulation driven by Kelvin-Helmholtz instability.