Efficacy and Safety of Re-administration of Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor (EGFR-TKI) After EGFR-TKI-Induced Interstitial Lung Disease (CS-Lung-005).

PURPOSE: This study investigated the safety and efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) re-administration after recovery from EGFR-TKI-induced interstitial lung disease (ILD). METHODS: This multicenter retrospective study collected data from consecutive advanced NSCLC patients who underwent EGFR-TKI re-administration after recovery from EGFR-TKI-induced ILD. RESULTS: Fifty-eight patients were registered. The grades of initial TKI-induced ILD were grade 1 to 4. TKIs used for re-administration were erlotinib for 15 patients, osimertinib for 15, gefitinib for 14, afatinib for 13 patients, and dacomitinib for 1 patient. ILD recurred in 13 patients (22.4%), comprising 3 patients with grade 1, 6 patients with grade 2, and 4 patients with grade 3. No significant associations were found between ILD recurrence and age, smoking history, performance status, time from initial ILD to TKI re-administration, or concomitant corticosteroid use. However, the incidence of ILD recurrence was high in cases of repeated use of gefitinib or erlotinib or first time use of osimertinib at TKI re-administration. The ILD recurrence rate was lowest in patients treated with first time use of gefitinib (8%) or erlotinib (8%), followed by patients treated with repeated use of osimertinib (9%). The response rate, median progression-free survival by TKI re-administration, and median overall survival were 55%, 9.6 and 84.8 months, respectively. CONCLUSION: This study showed that EGFR-TKI re-administration is a feasible and effective treatment for patients who recovered from EGFR-TKI-induced ILD. Our results indicate that re-administration of EGFR-TKI is an important option for long-term prognosis after recovery from EGFR-TKI-induced ILD.

Stepwise Treatment for TAFRO Syndrome.

TAFRO syndrome, a rapidly progressive and fatal disease, is rare, and its etiology remains unknown. It is characterized by thrombocytopenia, anasarca (edema, pleural effusion, and ascites), fever, reticulin fibrosis (or renal insufficiency), and organomegaly with Castleman disease (CD)-like histological features in the lymph nodes. CD is a rare, indolent, lymphoproliferative disorder with no established curative strategies. Most idiopathic multicentric CD cases are controlled with anti-interleukin (IL)-6 therapy (tocilizumab and siltuximab) and/or rituximab. However, it is unclear whether these therapies can be directly applied to treat TAFRO syndrome. Here, we describe stepwise immunotherapy (rituximab induction therapy and cyclosporine maintenance therapy) for two cases of steroid-refractory TAFRO syndrome. A 32-year-old man visited a local hospital with sudden onset of fever and epigastralgia. The diagnosis of TAFRO syndrome was established based on the diagnostic criteria. After rituximab administration, C-reactive protein and IL-6 levels were normalized. However, the ascites persisted, with increased resistance to rituximab. Tocilizumab was also ineffective; therefore, cyclosporine was administered. After the initiation of cyclosporine treatment, the ascites decreased and ultimately disappeared. Twelve months after immunotherapy, the patient remained asymptomatic under cyclosporine maintenance therapy. Similar stepwise immunosuppressive therapy was administered to a 72-year-old man with TAFRO syndrome complicated by renal failure. After rituximab infusion, C-reactive protein was decreased. Although methylprednisolone, rituximab, tocilizumab, and cyclosporine were administered, other laboratory data and clinical symptoms remained unchanged. His level of consciousness subsequently deteriorated due to herpes zoster encephalitis, and he died. We consider the combination of rituximab induction therapy and cyclosporine maintenance therapy to be effective for TAFRO syndrome if initiated at an early stage.

Transcranial Doppler ultrasonography detects the elevation of cerebral blood flow during ictal-phase of pentetrazol-induced seizures in dogs.

OBJECTIVE: To investigate the association between changes in cerebral blood flow and electrographic epileptic seizure in dogs using transcranial Doppler ultrasonography (TCD). ANIMALS: 6 healthy Beagle dogs. PROCEDURES: Each dog was administered pentetrazol (1.5 mg/kg/min) or saline (0.9% NaCl) solution under general anesthesia with continuous infusion of propofol. Both pentetrazol and saline solution were administered to all 6 dogs, with at least 28 days interval between the experiments. Blood flow waveforms in the middle cerebral artery and the basilar artery were obtained using TCD at baseline, after pentetrazol administration, and after diazepam administration. TCD velocities, including peak systolic velocity, end-diastolic velocity, and mean velocity and resistance variables, were determined from the Doppler waveforms. RESULTS: During ictal-phase of pentetrazol-induced seizures, the TCD velocities significantly increased in the basilar and middle cerebral arteries while TCD vascular resistance variables did not change in either artery. The TCD velocities significantly decreased after diazepam administration. Systemic parameters, such as the heart rate, mean arterial pressure, systemic vascular resistance, cardiac index, end-tidal carbon dioxide, oxygen saturation, and body temperature, did not change significantly during seizures. CLINICAL RELEVANCE: This study showed that cerebral blood flow, as obtained from TCD velocities, increased by 130% during ictal-phase of pentetrazol-induced seizures in dogs. The elevated velocities returned to baseline after seizure suppression. Thus, TCD may be used to detect electrographic seizures during the treatment of status epilepticus in dogs, and further clinical studies clarifying the association between changes in cerebral blood flow and non-convulsive seizure cases are needed.

Cardiovascular effects of dose escalating of norepinephrine in healthy dogs anesthetized with isoflurane.

OBJECTIVE: To evaluate the systemic cardiovascular effects of dose escalating administration of norepinephrine in healthy dogs anesthetized with isoflurane. STUDY DESIGN: Experimental study. ANIMALS: A total of six adult laboratory Beagle dogs, 10.5 (9.2-12.0) kg [median (range)]. METHODS: Each dog was anesthetized with isoflurane at an end-tidal concentration of 1.7%, mechanically ventilated and administered a continuous rate infusion of rocuronium (0.5 mg kg-1 hour-1). Each dog was administered incremental dose rates of norepinephrine (0.05, 0.125, 0.25, 0.5, 1.0 and 2.0 µg kg-1 minute-1), and each dose was infused for 15 minutes. Cardiovascular variables were recorded before administration and at the end of each infusion period. RESULTS: Norepinephrine infusion increased mean arterial pressure (MAP), cardiac output (CO) and oxygen delivery in a dose-dependent manner. Systemic vascular resistance did not significantly change during the experiment. Stroke volume increased at the lower dose rates and heart rate increased at the higher dose rates. Oxygen consumption and lactate concentrations did not significantly change during infusions. CONCLUSIONS: In dogs anesthetized with isoflurane, norepinephrine increased MAP by increasing the CO. CO increased with a change in stroke volume at lower dose rates of norepinephrine. At higher dosage, heart rate also contributed to an increase in CO. Norepinephrine did not cause excessive vasoconstriction that interfered with the CO during this study. CLINICAL RELEVANCE: Norepinephrine can be useful for treating hypotension in dogs anesthetized with isoflurane.

The mitochondrial Ca2+ uptake regulator, MICU1, is involved in cold stress-induced ferroptosis.

Ferroptosis has recently attracted much interest because of its relevance to human diseases such as cancer and ischemia-reperfusion injury. We have reported that prolonged severe cold stress induces lipid peroxidation-dependent ferroptosis, but the upstream mechanism remains unknown. Here, using genome-wide CRISPR screening, we found that a mitochondrial Ca2+ uptake regulator, mitochondrial calcium uptake 1 (MICU1), is required for generating lipid peroxide and subsequent ferroptosis under cold stress. Furthermore, the gatekeeping activity of MICU1 through mitochondrial calcium uniporter (MCU) is suggested to be indispensable for cold stress-induced ferroptosis. MICU1 is required for mitochondrial Ca2+ increase, hyperpolarization of the mitochondrial membrane potential (MMP), and subsequent lipid peroxidation under cold stress. Collectively, these findings suggest that the MICU1-dependent mitochondrial Ca2+ homeostasis-MMP hyperpolarization axis is involved in cold stress-induced lipid peroxidation and ferroptosis.

Molecular functions of ASK family in diseases caused by stress-induced inflammation and apoptosis.

VCells are constantly exposed to various types of stress, and disruption of the proper response leads to a variety of diseases. Among them, inflammation and apoptosis are important examples of critical responses and should be tightly regulated, as inappropriate control of these responses is detrimental to the organism. In several disease states, these responses are abnormally regulated, with adverse effects. Apoptosis signal-regulating kinase (ASK) family members are stress-responsive kinases that regulate inflammation and apoptosis after a variety of stimuli, such as oxidative stress and endoplasmic reticulum stress. In this review, we summarize recent reports on the ASK family in terms of their involvement in inflammatory diseases, focussing on upstream stimuli that regulate ASK family members.

Effects of immunosuppressive prednisolone therapy on pancreatic tissue and concentration of canine pancreatic lipase immunoreactivity in healthy dogs.

The objective of this study was to examine the effects of immunosuppressive prednisolone therapy on pancreatic tissue and the concentration of serum canine pancreatic lipase immunoreactivity (cPLI) in healthy dogs. Six healthy beagle dogs were subcutaneously administered an immunosuppressive dose of prednisolone [4 mg/kg body weight (BW)] once daily for either 2 or 3 weeks. Serum cPLI concentration was measured before and after treatment. Ultrasonographic examination of the pancreas and laparoscopic biopsy and histopathological examination of the right pancreatic lobe and the liver were also conducted before and after treatment. The expression of pancreatic lipase messenger ribonucleic acid (mRNA) in the pancreas and liver was examined by polymerase chain reaction (PCR). Although the serum cPLI concentration was significantly higher on day 14 and on the day of the second laparoscopy than before treatment, it was classified as normal (≤ 200 µg/L) in 5 dogs and as abnormal (≥ 400 µg/L) in only 1 dog. None of the 6 dogs showed clinical signs of pancreatitis during the study period. After treatment, ultrasonographic examination of the pancreas showed no changes except for a hypoechoic pancreas in 1 dog. Histopathological examination of the right pancreatic lobe in all dogs showed no evidence of pancreatitis after treatment. Pancreatic lipase mRNA expression was detected in the pancreas, but not in the liver, before and after treatment. The administration of 4 mg/kg BW per day of prednisolone for 2 or 3 weeks increased the serum cPLI concentration without clinical signs of pancreatitis, although an abnormal cPLI concentration (≥ 400 µg/L) was observed in only 1 dog. No ultrasonographic or histological evidence of pancreatitis was observed in any of the dogs.

L'objectif de la présente étude était d'examiner les effets d'une thérapie immunosuppressive par la prednisolone sur le tissu pancréatique et la concentration sérique canine de lipase pancréatique immunoréactive (cPLI) chez des chiens en santé. Six chiens beagle en santé ont reçu par voie sous-cutanée une dose immunosuppressive de prednisolone [4 mg/kg de poids corporel (PC)] une fois par jour pendant 2 ou 3 semaines. La concentration sérique de cPLI a été mesurée avant et après le traitement. Un examen échographique du pancréas et une biopsie suivie d'un examen histopathologique d'échantillons du lobe pancréatique droit ainsi que du foie obtenus par laparoscopie ont également été faits avant et après le traitement. L'expression de l'ARNm de la lipase pancréatique dans le pancréas et le foie a été examinée par réaction d'amplification en chaine par la polymérase. Bien que la concentration sérique de cPLI fût significativement plus élevée au jour 14 et le jour de la seconde laparoscopie qu'avant le traitement, elle était classée comme normale (≤ 200 µg/L) chez cinq chiens et comme anormale (≥ 400 µg/L) chez seulement un chien. Aucun des six chiens n'a présenté de signes cliniques de pancréatite durant la période d'étude. Après le traitement, l'examen échographique du pancréas ne démontrait aucun changement sauf pour un pancréas hypoéchogène chez un chien. L'examen histopathologique du lobe pancréatique droit chez tous les chiens n'a pas permis de mettre en évidence de pancréatite après le traitement. L'expression d'ARNm de lipase pancréatique fut détectée dans le pancréas, mais pas dans le foie, avant et après le traitement. L'administration de 4 mg/kg de PC par jour de prednisolone pendant 2 ou 3 semaines a fait augmenter la concentration sérique de cPLI sans signe clinique de pancréatite, bien qu'une concentration anormale de cPLI (≥ 400 µg/L) fût obtenue chez un chien. Aucune évidence échographique ou histologique de pancréatite ne fût observée chez les chiens de cette étude.(Traduit par Docteur Serge Messier).

Experimental and Theoretical Studies on Oxidation of Cu-Au Alloy Surfaces: Effect of Bulk Au Concentration.

We report results of our experimental and theoretical studies on the oxidation of Cu-Au alloy surfaces, viz., Cu3Au(111), CuAu(111), and Au3Cu(111), using hyperthermal O2 molecular beam (HOMB). We observed strong Au segregation to the top layer of the corresponding clean (111) surfaces. This forms a protective layer that hinders further oxidation into the bulk. The higher the concentration of Au in the protective layer formed, the higher the protective efficacy. As a result, of the three Cu-Au surfaces studied, Au3Cu(111) is the most stable against dissociative adsorption of O2, even with HOMB. We also found that this protective property breaks down for oxidations occurring at temperatures above 300 K.

Magnetic domain patterns on strong perpendicular magnetization of Co/Ni multilayers as spintronics materials: I. Dynamic observations.

Materials with perpendicular magnetic anisotropy can reduce the threshold current density of the current-induced domain wall motion. Co/Ni multilayers show strong perpendicular magnetic anisotropy and therefore it has become a highly potential candidate of current-induced domain wall motion memories. However, the details of the mechanism which stabilizes the strong perpendicular magnetization in Co/Ni multilayers have not yet been understood. In the present work, the evolution of the magnetic domain structure of multilayers consisting of pairs of 2 or 3 monolayers (ML) of Ni and 1 ML of Co on W(110) was investigated during growth with spin-polarized low-energy electron microscopy. An interesting phenomenon, that the magnetic domain structure changed drastically during growth, was revealed. In the early stages of the growth the magnetization alternated between in-plane upon Co deposition and out-of-plane upon Ni deposition. The change of the magnetization direction occurred within a range of less than 0.2 ML during Ni or Co deposition, with break-up of the existing domains followed by growth of new domains. The Ni and Co thickness at which the magnetization direction switched shifted gradually with the number of Co/Ni pairs. Above 3-4 Co/Ni pairs it stayed out-of-plane. The results indicate clearly that the Co-Ni interfaces play the important role of enhancing the perpendicular magnetic anisotropy.

Magnetic domain patterns on strong perpendicular magnetization of Co/Ni multilayers as spintronics materials: II. Numerical simulations.

Magnetic domains in ultrathin films form domain patterns, which strongly depend on the magnetic anisotropy. The magnetic anisotropy in Co/Ni multilayers changes with the number of layers. We provide a model to simulate the experimentally observed domain patterns. The model assumes a layer-dependent magnetic anisotropy. With the anisotropy parameter estimated from experimental data, we reproduce the magnetic domain patterns.