Lower-Extremity Torque Capacity and Physical Function in Mobility-Limited Older Adults.

OBJECTIVES: Skeletal muscle weakness and an increase in fatigability independently contribute to age-related functional decline. The objective of this study was to examine the combined contribution of these deficiencies (i.e., torque capacity) to physical function, and then to assess the functional implications of progressive resistance training (PRT) mediated-torque capacity improvements in mobility-limited older adults. DESIGN: Randomized controlled trial. SETTING: Exercise laboratory on the Health Sciences campus of an urban university. PARTICIPANTS: Seventy mobility-limited (Short Physical Performance Battery (SPPB) ≤9) older adults (~79 yrs). INTERVENTION: Progressive resistance training or home-based flexibility 3 days/week for 12 weeks. MEASUREMENTS: Torque capacity was defined as the sum of peak torques from an isokinetic knee extension fatigue test. Relationships between torque capacity and performance-based and patient-reported functional measures before and after PRT were examined using partial correlations adjusted for age, sex, and body mass index. RESULTS: Torque capacity explained (P<0.05) 10 and 28% of the variance in six-minute walk distance and stair climb time, respectively. PRT-mediated torque capacity improvements were paralleled by increases (P<0.05) in self-reported activity participation (+20%) and advanced lower extremity function (+7%), and associated (P<0.05) with a reduction in activity limitations (r=0.44) and an improved SPPB score (r=0.32). CONCLUSION: Skeletal muscle torque capacity, a composite of strength and fatigue, may be a proximal determinant of physical function in mobility-limited older individuals. To more closely replicate the musculoskeletal demands of real-life tasks, future studies are encouraged to consider the combined interaction of distinct skeletal muscle faculties to overall functional ability in older adults.

Cost-effectiveness and safety of the molecular targeted drugs afatinib, gefitinib and erlotinib as first-line treatments for patients with advanced EGFR mutation-positive non-small-cell lung cancer.

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), including gefitinib, erlotinib and afatinib are standard first-line treatments for EGFR gene mutation-positive non-small cell lung cancer. The present study aimed to compare the cost-effectiveness of using erlotinib, afatinib or gefitinib. The safety of EGFR-TKIs was also investigated. Expected costs were calculated based on data from patients with advanced EGFR mutation-positive non-small-cell lung cancer who were treated with gefitinib, erlotinib or afatinib. Literature was collected to obtain the necessary clinical information for calculating the probability and the validity of each chemotherapy. Median survival time (MST) was used to evaluate the therapeutic effect of the regimens. The cost-effectiveness ratio was calculated using expected costs and MSTs for the three regimens. The cost-effectiveness ratio per month was JPY 386,859.4/MST for afatinib, JPY 264,788.7/MST for gefitinib and JPY 397,039.9/MST for erlotinib. Significant differences were observed between the three groups (p<0.001). The incremental cost-effectiveness ratio (ICER) of gefitinib compared with afatinib per month was JPY 122,070.7/MST. The ICER of gefitinib compared with erlotinib was JPY -69,605.9/MST. Adverse effects of Grade 3 and higher, including diarrhoea (28.6%) and paronychia (14.3%) were observed in the afatinib treatment group. Paronychia (23.1%) was observed in the erlotinib treatment group, while none were observed in the gefitinib treatment group. These findings demonstrate that gefitinib is more cost effective in comparison with the afatinib and erlotinib regimens, although the afatinib and erlotinib regimens were well-tolerated and produce sufficient effects.

Evaluation of the safety of ramucirumab in Japanese patients with advanced gastric cancer.

As a result of the RAINBOW trial, ramucirumab plus paclitaxel was established as a second-line treatment of advanced gastric cancer. Regarding the safety of ramucirumab plus paclitaxel in the Japanese, a subgroup analysis of the RAINBOW trial was conducted. The incidence of neutropenia was higher in Japanese patients. However, information is lacking concerning the safety of ramucirumab after marketing in Japanese patients. Therefore, the aim of this study was to evaluate the safety of ramucirumab in Japanese patients with advanced gastric cancer. The inclusion criteria were patients diagnosed with advanced gastric cancer who had commenced treatment with ramucirumab plus paclitaxel or paclitaxel only at Ogaki Municipal Hospital (Gifu, Japan) between January 2015 and December 2016. There were 26 patients in the ramucirumab plus paclitaxel group and 22 patients in the paclitaxel only group. Treatment-related adverse events were documented in 100.0% of the patients in the ramucirumab plus paclitaxel group (Grade 3-4, 73.1%) and 90.9 % of the patients in the paclitaxel only group (Grade 3-4, 45.5 %). The most frequently observed adverse event in both treatment groups was anemia. The second common adverse event was neutropenia. The incidence of neutropenia of Grade ≥3 was significantly higher in the ramucirumab plus paclitaxel group than in the paclitaxel only group. In conclusion, the incidence of neutropenia is high. However, we believe that ramucirumab plus paclitaxel can be safely administered.

Risk factors contributing to the development of neutropenia in patients receiving oral trifluridine-tipiracil (TAS-102) chemotherapy for advanced/recurrent colorectal cancer.

Elucidating the factors influencing severe neutropenia could aid in earlier management of neutropenia during oral trifluridine-tipiracil (TAS-102) chemotherapy in advanced and recurrent colorectal cancer (CRC). This study was conducted to assess the risk of TAS-102-induced grade 3 or more neutropenia. Between August 2014 and July 2017, 60 patients underwent oral TAS-102 monotherapy at Ogaki Municipal Hospital, Japan. The patients were divided into two groups based on the development of grade 3 or more neutropenia (9 patients) or not (51 patients). Risk factors for grade 3 or more neutropenia were examined by univariate and multivariate analyses. Creatinine clearance rate (CrCl) before TAS-102 administration significantly correlated with the incidence of Grade 3 or more neutropenia after TAS-102 administration (odds ratio 6.5, 95% confidence interval 1.14-30.00; p = 0.02). Multivariate analysis revealed that a CrCl of lower than 57.1 mL/min before TAS-102 administration (odds ratio 54.06, 95% confidence interval 2.14-1364.2; p = 0.02) was an independent risk factor significantly contributing to the development of grade 3 or more neutropenia, induced by TAS-102. CrCl < 57.1 mL/min in patients with advanced and recurrent CRC who underwent TAS-102 chemotherapy was associated with grade 3 or more neutropenia.

Prognostic factors in patients with advanced and recurrent colorectal cancer receiving last-line chemotherapy.

For patients with advanced/recurrent colorectal cancer, the trifluridine/tipiracil combination tablet (TAS 102) and regorafenib are last-line treatments. This study aimed to clarify prognostic factors in patients receiving last-line chemotherapy. Between April 2014 and December 2016, 47 patients received last-line chemotherapy at Ogaki Municipal Hospital, Japan. The primary outcome was overall survival. To determine factors associated with survival, those considered significant in the univariate analysis (p <0.10), were entered into a multivariate Cox proportional hazards model. KRAS type and the use of opioid formulations were independently and significantly associated with survival in the multivariate analysis. For patients with KRAS-wild relative to KRAS-mutation cancers, the hazard ratio for death was 0.478 (95% CI, 0.249-0.919; p = 0.03). For patients taking opioid formulations, relative to those not, the hazard ratio for death was 3.557 (95% CI, 1.032-12.257; p = 0.04). The median overall survival duration for patients with KRAS-wild (n = 24) and KRAS-mutation (n = 23) cancers were 223.5 days (range: 115-703) and 154 days (range: 51-503), respectively (p = 0.05). This finding provides a useful index to make an early decision on discontinuation of treatment and to guide decisions around agents to use in last-line chemotherapy.

Mutual relationships between structural and functional changes in a PsbM-deletion mutant of photosystem II.

Photosystem II (PSII) is a membrane protein complex that performs light-induced electron transfer and oxygen evolution from water. PSII consists of 19 or 20 subunits in its crystal form and binds various cofactors such as chlorophyll a, plastoquinone, carotenoid, and lipids. After initial light excitation, the charge separation produces an electron, which is transferred to a plastoquinone molecule (QA) and then to another plastoquinone (QB). PsbM is a low-molecular-weight subunit with one transmembrane helix, and is located in the monomer-monomer interface of the PSII dimer. The function of PsbM has been reported to be stabilization of the PSII dimer and maintenance of electron transfer efficiency of PSII based on previous X-ray crystal structure analysis at a resolution of 4.2 Å. In order to elucidate the structure-function relationships of PsbM in detail, we improved the quality of PSII crystals from a PsbM-deleted mutant (ΔPsbM-PSII) of Thermosynechococcus elongatus, and succeeded in improving the diffraction quality to a resolution of 2.2 Å. X-ray crystal structure analysis of ΔPsbM-PSII showed that electron densities for the PsbM subunit and neighboring carotenoid and detergent molecules were absent in the monomer-monomer interface. The overall structure of ΔPsbM-PSII was similar to wild-type PSII, but the arrangement of the hydrophobic transmembrane subunits was significantly changed by the deletion of PsbM, resulting in a slight widening of the lipid hole involving QB. The lipid hole-widening further induced structural changes of the bicarbonate ion coordinated to the non-heme Fe(ii) atom and destabilized the polypeptide chains around the QB binding site located far from the position of PsbM. The fluorescence decay measurement indicated that the electron transfer rate from QA to QB was decreased in ΔPsbM-PSII compared with wild-type PSII. The functional change in electron transfer efficiency was fully interpreted based on structural changes caused by the deletion of the PsbM subunit.

TTF-1/NKX2-1 binds to DDB1 and confers replication stress resistance to lung adenocarcinomas.

TTF-1, also known as NKX2-1, is a transcription factor that has indispensable roles in both lung development and physiology. We and others have reported that TTF-1 frequently exhibits high expression with increased copy number in lung adenocarcinomas, and also has a role as a lineage-survival oncogene through transcriptional activation of crucial target genes including ROR1 and LMO3. In the present study, we employed a global proteomic search for proteins that interact with TTF-1 in order to provide a more comprehensive picture of this still enigmatic lineage-survival oncogene. Our results unexpectedly revealed a function independent of its transcriptional activity, as TTF-1 was found to interact with DDB1 and block its binding to CHK1, which in turn attenuated ubiquitylation and subsequent degradation of CHK1. Furthermore, TTF-1 overexpression conferred resistance to cellular conditions under DNA replication stress (RS) and prevented an increase in consequential DNA double-strand breaks, as reflected by attenuated induction of pCHK2 and γH2AX. Our findings suggest that the novel non-transcriptional function of TTF-1 identified in this study may contribute to lung adenocarcinoma development by conferring tolerance to DNA RS, which is known to be inherently elicited by activation of various oncogenes.

Dimensional contraction by principal component analysis as preprocessing for independent component analysis at MCG.

We propose a noise reduction method for magnetocardiograms (MCGs) based on independent component analysis (ICA). ICA is useful to separate the noise and signal components, but ICA-based automatic noise reduction faces two main difficulties: the dimensional contraction process applied after the principal component analysis (PCA) used for preprocessing, and the component selection applied after ICA. The results of noise reduction vary among people, because these two processes typically depend on personal qualitative evaluations of the obtained components. Therefore, automatic quantitative ICA-based noise reduction is highly desirable. We will focus on the first difficulty, by improving the index used in the dimensional contraction process. The index used for component ordering after PCA affects the accuracy of separation obtained with ICA. The contribution ratio is often used as an index. However, its efficacy is highly dependent on the signal-to-noise ratio (SNR) it unsuitable for automation. We propose a kurtosis-based index, whose efficacy does not depend on SNR. We compare the two decision indexes through simulation. First, we evaluate their preservation rate of the MCG information after dimensional contraction. In addition, we evaluate their effect on the accuracy of the ICA-based noise reduction method. The obtained results show that the kurtosis-based index does preserve the MCG signal information through dimensional contraction, and has a more consistent behavior when the number of components increases. The proposed index performs better than the traditional index, especially in low SNRs. As such, it paves the way for the desired noise reduction process automation.

Severe neutropenia: a prognosticator in patients with advanced/recurrent colorectal cancer under oral trifluridine-tipiracil (TAS-102) chemotherapy.

BACKGROUND/AIM: The effect of oral trifluridine-tipiracil (TAS-102)-induced neutropenia on survival of patients with advanced/recurrent colorectal cancer was investigated. PATIENTS AND METHODS: Between August 2014 and May 2016, 41 patients underwent TAS-102 monotherapy at Ogaki Municipal Hospital. Risk factors for survival were examined by univariate and multivariate analyses. RESULTS: In 41 patients, mild neutropenia (grade 1-2) occurred in 10 patients (24.4%), severe neutropenia (grade 3-4) occurred in 13 (31.7%), and 18 (43.9%) did not experience neutropenia. The median overall survival times in the absent, mild, and severe groups were 120 days (95% confidence interval [CI], 67-179), 184 days (95% CI, 94-274), and 299 days (95% CI, 192-404), respectively (p = 0.045). In patients with severe neutropenia, the death hazard ratio was 0.442 (95% CI, 0.201-0.974; p = 0.042). CONCLUSION: In patients with advanced/recurrent colorectal cancer, TAS-102-induced severe neutropenia was associated with superior survival.

Safety of an oral anticancer agent (trifluridine/tipiracil combination tablet) in patients with advanced and recurrent colorectal cancer.

We retrospectively studied the safety of trifluridine/tipiracil combination tablet (TAS-102) monotherapy in patients with advanced and recurrent colorectal cancer. Adverse events to TAS-102 monotherapy were observed in 22 out of 23 cases (95.7%). The most frequent adverse events were neutropenia (69.6%), nausea (53.2%), and malaise (30.4%). Treatment was postponed in 54 (59.3%) out of 91 courses, and in 34 (66.7%) of these 54 courses, the delay in treatment was due to bone marrow suppression. Seven patients with peritoneal metastases suffered from nausea, whilst none of the patients without peritoneal metastases had nausea (p = 0.0139). Nausea and vomiting during a previous chemotherapy cycle was significantly associated with nausea after TAS-102 treatment (p = 0.0007), and the treatment cycles were significantly longer in patients with grade 3 or 4 neutropenia (p = 0.0061). Our results suggest that the incidence of nausea was higher in patients treated with TAS-102. Therefore, it is important to inform patients of the risk of these toxicities and to provide enhanced supportive care. Moreover, we recommend that, for patients with repeated treatment postponement due to neutropenia, the dosage should be fixed based on therapeutic efficacy and prognosis.

In vivo eradication of MLL/ENL leukemia cells by NK cells in the absence of adaptive immunity.

It remains unclear how the immune system affects leukemia development. To clarify the significance of the presence of immune systems in leukemia development, we transferred MLL/ENL leukemia cells into immune-competent or immune-deficient mice without any preconditioning including irradiation. The wild-type mice did not develop leukemia, whereas all the Rag2(-/-)γc(-/-) mice lacking both adaptive immune cells and natural killer (NK) cells developed leukemia, indicating that leukemia cells were immunologically rejected. Interestingly, leukemia cells were also rejected in 60% of the Rag2(-/-) mice that lacked adaptive immune cells but possessed NK cells, suggesting that NK cells play a substantial role in the rejection of leukemia. Moreover, engraftment of leukemia cells was enhanced by NK cell depletion in Rag2(-/-) recipients and inhibited by transfer of NK cells into Rag2(-/-)γc(-/-) recipients. Upregulation of NKG2D (NK group 2, member D) ligands in MLL/ENL leukemia cells caused elimination of leukemia cells by NK cells. Finally, we found that leukemia cells resistant to elimination by NK cells had been selected during leukemia development in Rag2(-/-) recipients. These results demonstrate that NK cells can eradicate MLL/ENL leukemia cells in vivo in the absence of adaptive immunity, thus suggesting that NK cells can play a potent role in immunosurveillance against leukemia.

Transgenic overproduction of omega-3 polyunsaturated fatty acids provides neuroprotection and enhances endogenous neurogenesis after stroke.

Strokes are devastating as there are no current therapies to prevent the long term neurological deficits that they cause. Soon after ischemic stroke, there is proliferation and differentiation of neural stem/progenitor cells as an important mechanism for neuronal restoration. However, endogenous neurogenesis by itself is insufficient for effective brain repair after stroke as most newborn neurons do not survive. One fascinating strategy for stroke treatment would thus be maintaining the survival and/or promoting the differentiation of endogenous neural stem/progenitor cells. Using transgenic (Tg) mice over-expressing the C. elegans fat-1 gene encoding an enzyme that converts endogenous omega-6 to omega-3 polyunsaturated fatty acids (n-3 PUFAs), we showed that fat-1 Tg mice with chronically elevated brain levels of n-3 PUFAs exhibited less brain damage and significantly improved long-term neurological performance compared to wild type littermates. Importantly, post-stroke neurogenesis occurred more robustly in fat-1 Tg mice after focal ischemia. This was manifested by enhanced neural stem cell proliferation/differentiation and increased migration of neuroblasts to the ischemic sites where neuroblasts matured into resident neurons. Moreover, these neurogenic effects were accompanied by significantly increased oligodendrogenesis. Our results suggest that n-3 PUFA supplementation is a potential neurogenic and oligodendrogenic treatment to naturally improve post-stroke brain repair and long-term functional recovery.

High incidence of secondary failure of platelet recovery after autologous and syngeneic peripheral blood stem cell transplantation in acute promyelocytic leukemia.

Secondary failure of platelet recovery (SFPR), which is a delayed decline in platelet count after primary recovery following myeloablative hematopoietic SCT, is a significant problem in allogeneic SCT. However, its clinical characteristics have not been well described in autologous SCT for acute myeloid leukemia. We reviewed 11 consecutive patients who had received autologous or syngeneic SCT for acute promyelocytic leukemia. Seven of 11 patients (64%) had SFPR, which is defined as a decline in the platelet count to less than 30,000/microl for more than 7 days. The median onset of SFPR was day 36 (range, 25-51 days) and the median duration of thrombocytopenia was 13 days (range, 4-25 days). Of nine patients who received busulfan-containing preparative regimens, seven (78%) had SFPR and one had delayed primary platelet count recovery. Neither patient who received cyclophosphamide and total body irradiation as preparative regimens had SFPR. The clinical courses of SFPR were transient and self-limited. SFPR was not associated with relapse of underlying diseases, graft failure or other fatal morbidities. The unexpectedly high prevalence and the characteristics of SFPR may provide additional information on management following autologous SCT for acute myeloid leukemia.

Assessment of efficacy of a live oral poliovirus vaccine for virulent Sabin-like poliovirus 1 strains in Japan.

Virulent Sabin-like poliovirus (VSLP) was isolated from river and sewage waters between October 1993 and September 1995 in Toyama Prefecture, Japan (Yoshida et al., Lancet 356, 1461-1463, 2000). In this study, to assess the possibility of an epidemic of poliomyelitis caused by a VSLP in Japan under the current vaccination policy of administration of live attenuated oral poliovirus vaccine (OPV), we determined titers of serum neutralizing antibodies to poliovirus 1 (PV-1) strains Sabin (vaccine strain), Mahoney (wild-type strain) and G4-12 (VSLP) in various groups of residents of Toyama Prefecture, Japan. The seropositivity and geometric mean neutralizing antibody titers against these strains in the individuals who obtained two doses of OPV were 99.1%, 94.5% and 95.5%, respectively, and 564, 186 and 194, respectively. Although the antibody titers to G4-12 were lower compared with those to Sabin, these results indicate that the OPV vaccination policy in Japan has been effective in preventing poliomyelitis caused by VSLPs. These results also suggest that (i) an epidemic of poliomyelitis caused by a VSLP has not occurred in Japan due to herd immunity, and (ii) the possibility of reemergence of VSLPs will be prevented if sufficient herd immunity is acquired immediately after completion of the OPV vaccination in accordance with the poliomyelitis eradication program.

Interacting molecule of AT1 receptor, ATRAP, is colocalized with AT1 receptor in the mouse renal tubules.

The renin-angiotensin system in the kidney plays a critical role in the regulation of renal hemodynamics and sodium handling through the activation of vascular, glomerular and tubular angiotensin II type 1 (AT1) receptor-mediated signaling. We previously cloned a molecule that specifically bound to the AT1 receptor and modulated AT1 receptor signaling in vitro, which we named ATRAP (for AT1 receptor-associated protein). The purpose of this study is to analyze the renal distribution of ATRAP and to examine whether ATRAP is co-expressed with the AT1 receptor in the mouse kidney. We performed in situ hybridization, Western blot analysis, and immunohistochemistry to investigate the expression of ATRAP mRNA and protein in the mouse kidney. The results of Western blot analysis revealed the ATRAP protein to be abundantly expressed in the kidney. Employing in situ hybridization and immunohistochemistry, we found that both ATRAP mRNA and the protein were widely distributed along the renal tubules from Bowman's capsules to the inner medullary collecting ducts. ATRAP mRNA was also detected in the glomeruli, vasculature, and interstitial cells. In all tubular cells, the ATRAP protein colocalized with the AT1 receptor. Finally, we found that the dietary salt depletion significantly decreased the renal expression of ATRAP as well as AT1 receptor. These findings show ATRAP to be abundantly and broadly distributed in nephron segments where the AT1 receptor is expressed. Furthermore, this is the first report demonstrating a substantial colocalization of ATRAP and AT1 receptor in vivo.

[Rapidly enlarging giant left ventricular pseudo-false aneurysm after myocardial infarction; report of a case].

A 71-year-old man was admitted to our hospital with acute myocardial infarction and cardiac tamponade. After pericardial drainage, his hemodynamics was improved. Because more than 3 days had been passed after the onset of myocardial infarction and he had severe renal dysfunction, emergent coronary angiography (CAG) was not performed. After improvement of his general status, coronary angiography and percutaneous catheter intervention was carried out, and his course was uneventful. But transthoracic echocardiography before discharge revealed a giant posterior psudoaneurysm. Patch closure and coronary artery bypass grafting was carried out under cardiopulmonary bypass, and postoperative course was uneventful. Postoperative left ventriculogram revealed disappearance of pseudoaneurysm, but relatively large akinetic area of posterior-inferior wall was left around a patch. Pseudo-false aneurysm was diagnosed by histological examination.

Expression and methylation status of the FHIT gene in acute myeloid leukemia and myelodysplastic syndrome.

To clarify the role of fragile histidine triad (FHIT) in hematological malignancies, we examined the methylation status and the expression level of the FHIT gene in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) cells in comparison with the methylation of the p15(INK4B) gene. The FHIT methylation was found in 13 of 94 (13.8%) AML and 22 of 40 (55.0%) MDS cases, but not in normal mononuclear cells (MNCs). Both the frequency and density of methylation increased in the advanced-stages MDS and the relapsed AML cases. Although FHIT and p15(INK4B) methylations were not correlated in MDS and AML, increased FHIT methylation at the relapse in AML was associated with p15(INK4B) methylation. The median expression level in AML was significantly higher than in normal MNCs, although the median expression level in those with methylation was significantly lower than in those without methylation. Furthermore, the methylation level at relapse was significantly higher than at diagnosis in AML. These results suggested that FHIT methylation was accumulated through the disease progression of MDS and AML, and the role of the FHIT gene as a tumor suppressor seemed different in AML and MDS.

Serious cardiac and pulmonary calcification in a young peritoneal dialysis patient: potential role of continuous correction of acidosis.

We describe a 40-month-old male infant with renal failure, treated with peritoneal dialysis, who developed massive calcification of soft tissues including the heart and lungs with subsequent cardiopulmonary insufficiency. A diagnosis of Jeune syndrome was made. After starting peritoneal dialysis, the patient exhibited an intractable metabolic acidosis of unknown etiology necessitating treatment with intravenous or oral sodium bicarbonate. Myocardial calcification was first detected by 2-dimensional echocardiography performed 3 months after starting dialysis. The patient was not suitable for renal transplantation because of his cardiac dysfunction and died of cardiac and respiratory failure at the age of 6 years. Although the patient exhibited a variety of risk factors for ectopic calcification including hyperphosphatemia, hyperparathyroidism, high calcium-phosphate product and treatment with vitamin D, the early and massive soft tissue calcification may have been accelerated by correction of the metabolic acidosis. Therefore, the use of sodium bicarbonate may be involved in the etiology of the myocardial calcification.