Background
The prognosis for marginally resectable gastric cancer with extensive lymph node metastasis (ELM) remains unfavorable, even after R0 resection. To assess the safety and efficacy of ...preoperative docetaxel, oxaliplatin, and S-1 (DOS), we conducted a multicenter phase II trial.
Methods
Eligibility criteria included histologically proven HER2-negative gastric adenocarcinoma with bulky nodal (bulky N) involvement around major branched arteries or para-aortic node (PAN) metastases. Patients received three cycles of docetaxel (40 mg/m
2
, day 1), oxaliplatin (100 mg/m
2
, day 1), and S-1 (80–120 mg/body, days 1–14), followed by gastrectomy with D2 plus PAN dissection. Subsequently, patients underwent postoperative chemotherapy with S-1 for 1 year. The primary endpoint was major (grade ≥ 2a) pathological response rate (pRR) according to the Japanese Classification of Gastric Carcinoma criteria.
Results
Between October 2018 and March 2022, 47 patients (bulky N, 20; PAN, 17; both, 10) were enrolled in the trial. One patient was ineligible. Another declined any protocol treatments before initiation. Among the 45 eligible patients who initiated DOS chemotherapy, 44 (98%) completed 3 cycles and 42 (93%) underwent R0 resection. Major pRR and pathological complete response rates among the 46 eligible patients, including the patient who declined treatment, were 57% (26/46) and 24% (11/46), respectively. Common grade 3 or 4 toxicities were neutropenia (24%), anorexia (16%), febrile neutropenia (9%), and diarrhea (9%). No treatment-related deaths occurred.
Conclusions
Preoperative chemotherapy with DOS yielded favorable pathological responses with an acceptable toxicity profile. This multimodal approach is highly promising for treating gastric cancer with ELM.
Background
Neoadjuvant treatment is recommended for large GISTs due to their friability and risk of extensive operations; however, studies on the indications and long-term results of this approach ...are lacking.
Methods
Patients with large (≥ 10 cm) gastric GISTs were enrolled from multiple centers in Korea and Japan after a pathologic confirmation of c-KIT ( +) GISTs. Imatinib (400 mg/d) was given for 6–9 months preoperatively, and R0 resection was intended. Postoperative imatinib was given for at least 12 months and recommended for 3 years.
Results
A total of 56 patients were enrolled in this study, with 53 patients receiving imatinib treatment at least once and 48 patients undergoing R0 resection. The 5-year overall survival and progression-free survival rates were 94.3% and 61.6%, respectively. Even patients with stable disease by RECIST criteria responded well to preoperative imatinib treatment and could undergo R0 resection, with most being evaluated as partial response by CHOI criteria. The optimal reduction in tumor size was achieved with preoperative imatinib treatment for 24 weeks or more. No resumption of imatinib treatment was identified as an independent prognostic factor for recurrence after R0 resection. No additional size criteria for a higher risk of recurrence were identified in this cohort with a size of 10 cm or more.
Conclusions
Neoadjuvant imatinib treatment is an effective treatment option for gastric GISTs 10 cm or larger. Postoperative imatinib treatment is recommended even after R0 resection to minimize recurrence.
•Overexpression of BAALC is a poor prognostic factor in various types of leukemia.•We identified the actin-related protein Drebrin1 as a binding partner of BAALC.•The BAALC–Drebrin1 complex was found ...to contribute to the chemoresistance of cytarabine.•Disrupting this complex canceled its chemoresistance capacity.
BAALC is identified as a leukemia-associated gene and is highly expressed in CD34-positive hematopoietic stem cells. High BAALC expression is associated with poor prognosis in several types of acute myeloid leukemia. We explored binding partner proteins of BAALC by means of mass spectrometry and analyzed biological properties of BAALC-expressing leukemic cells. We found that BAALC physically interacts with DBN1, which is an actin-binding protein and promotes cell adhesion and mobility by forming cell membrane spines during cell–cell interactions. Drebrin1 downregulation impeded cell adhesion to bone marrow stromal cells, resulting in improvement of sensitivity to cytarabine. Taken together, our findings suggest that BAALC–DBN1 interaction contributes to the anchoring of BAALC-expressing cells in the bone marrow, which in turn leads to resistance to cytotoxic drugs. Therefore, the BAALC–DBN1 interaction provides us with an opportunity to overcome the chemotherapy resistance in BAALC-activated leukemia via functional blockage of these genes.
Human induced pluripotent stem cell-derived cardiomyocytes (iPS-CMs) provide a novel assay system to assess cardiac safety in drug development to overcome a problem of species difference in ...non-clinical testing during drug development. Using the multi-electrode array (MEA) platform, electrophysiological activities of iPS-CMs can be recorded easily to assess QT prolongation and proarrhythmic potential of drug candidates. Here we have established a standardized protocol to evaluate the possibility of iPS-CMs, and shared the protocol with an international consortium. To obtain reproducible and reliable experimental data from these cells, we determined the optimal experimental conditions, such as cell density, MEA coating, culture conditions, high-pass filter frequency, definition of early afterdepolarization or triggered activity, and calibration compounds. Based on the protocol, our validation study using 60 compounds is in progress. Thus, MEA-based experiments using iPS-CMs would be a standard testing method to evaluate QT prolongation and proarrhythmic potentials.
Streptococcus pyogenes, one of the major human pathogens, is a unique species since it has acquired diverse strain-specific virulence properties mainly through the acquisition of streptococcal ...prophages. In addition, S. pyogenes possesses clustered regularly interspaced short palindromic repeats (CRISPR)/Cas systems that can restrict horizontal gene transfer (HGT) including phage insertion. Therefore, it was of interest to examine the relationship between CRISPR and acquisition of prophages in S. pyogenes. Although two distinct CRISPR loci were found in S. pyogenes, some strains lacked CRISPR and these strains possess significantly more prophages than CRISPR harboring strains. We also found that the number of spacers of S. pyogenes CRISPR was less than for other streptococci. The demonstrated spacer contents, however, suggested that the CRISPR appear to limit phage insertions. In addition, we found a significant inverse correlation between the number of spacers and prophages in S. pyogenes. It was therefore suggested that S. pyogenes CRISPR have permitted phage insertion by lacking its own spacers. Interestingly, in two closely related S. pyogenes strains (SSI-1 and MGAS315), CRISPR activity appeared to be impaired following the insertion of phage genomes into the repeat sequences. Detailed analysis of this prophage insertion site suggested that MGAS315 is the ancestral strain of SSI-1. As a result of analysis of 35 additional streptococcal genomes, it was suggested that the influences of the CRISPR on the phage insertion vary among species even within the same genus. Our results suggested that limitations in CRISPR content could explain the characteristic acquisition of prophages and might contribute to strain-specific pathogenesis in S. pyogenes.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Mycobacterium abscessus species (MABS) is the most commonly isolated rapidly growing mycobacteria (RGM) and is one of the most antibiotic-resistant RGM with rapid progression, therefore, treatment of ...MABS is still challenging. We here presented a new combination treatment with sitafloxacin that targeted rough morphotypes of MABS, causing aggressive infections. Thirty-four clinical strains of MABS were isolated from various clinical samples at the Juntendo university hospital from 2011 to 2020. The susceptibility to a combination of sitafloxacin and antimicrobial agents was compared to that of the antimicrobial agents alone. Out of 34 MABS, 8 strains treated with sitafloxacin-amikacin combination, 9 of sitafloxacin-imipenem combination, 19 of sitafloxacin-arbekacin combination, and 9 of sitafloxacin-clarithromycin combination showed synergistic effects, respectively. Sitafloxacin-arbekacin combination also exhibited the synergistic effects against 10 of 22 Mycobacterium abscessus subspecies massiliense (Mma) strains and 8 of 11 Mycobacterium abscessus subspecies abscessus (Mab) strains, a highly resistant subspecies of MABS. The sitafloxacin-arbekacin combination revealed more synergistic effects in rough morphotypes of MABS (p = 0.008). We demonstrated the synergistic effect of the sitafloxacin-arbekacin combination against MABS. Further, this combination regimen might be more effective against Mab or rough morphotypes of MABS.
Infiltration of inflammatory macrophages into adipose tissues with the progression of obesity triggers insulin resistance and obesity-related metabolic diseases. We recently reported that ...macrophage-derived apoptosis inhibitor of macrophage (AIM) protein is increased in blood in line with obesity progression and is incorporated into adipocytes, thereby inducing lipolysis in adipose tissue. Here we show that such a response is required for the recruitment of adipose tissue macrophages. In vitro, AIM-dependent lipolysis induced an efflux of palmitic and stearic acids from 3T3-L1 adipocytes, thereby stimulating chemokine production in adipocytes via activation of toll-like receptor 4 (TLR4). In vivo administration of recombinant AIM to TLR4-deficient (TLR4â»/â») mice resulted in induction of lipolysis without chemokine production in adipose tissues. Consistently, mRNA levels for the chemokines that affect macrophages were far lower in AIM-deficient (AIMâ»/â») than in wild-type (AIMâº/âº) obese adipose tissue. This reduction in chemokine production resulted in a marked prevention of inflammatory macrophage infiltration into adipose tissue in obese AIMâ»/â» mice, although these mice showed more advanced obesity than AIMâº/⺠mice on a high-fat diet. Diminished macrophage infiltration resulted in decreased inflammation locally and systemically in obese AIMâ»/â» mice, thereby protecting them from insulin resistance and glucose intolerance. These results indicate that the increase in blood AIM is a critical event for the initiation of macrophage recruitment into adipose tissue, which is followed by insulin resistance. Thus, AIM suppression might be therapeutically applicable for the prevention of obesity-related metabolic disorders.
A tetrabutylammonium bromide (TBAB) hydrate is the only ionic semiclathrate hydrate that has been commercialized as a medium for efficient thermal energy storage targeting general air conditioning. ...However, TBAB is an environmental pollutant, while liquid water and ice that have been widely used as conventional media, also have difficulty in increasing the thermal energy storage density as well as the coefficient of performance (COP) of a refrigerator to form solid. In this study, a tetrabutylphosphonium phosphate ((TBP)3PO4) hydrate was proposed as an alternative green medium. The dissociation heat and the phase equilibrium temperature, which were both crucial factors to evaluate the thermal energy storage density, and COP was experimentally determined. It was found that the maximum dissociation heat was 154.1 ± 2.0 kJ･kg−1 at the mass fraction of 0.309. The highest phase equilibrium temperature was 10.0 °C at the mass fractions of 0.290, 0.299, and 0.309. The thermal energy storage density of (TBP)3PO4 hydrates was 3.7 times larger than that of water. (TBP)3PO4 hydrates increased the COP of a refrigerator to form solid by 42% as compared with ice, indicating the potential size-reduction of conventional devices with the decrease in the power consumption of a refrigerator. The effective balance between environmental protection and the system performance through (TBP)3PO4 hydrates was also discussed.
•The energy density of hydrate is 3.7 times larger than that of water.•The refrigerator to form hydrate has greater COP by 42% compared to ice.•The effective balance between environment protection and performance was discussed.
Familial platelet disorder (FPD) with predisposition to acute myelogenous leukaemia (AML) is characterized by platelet defects with a propensity for the development of haematological malignancies. ...Its molecular pathogenesis is poorly understood, except for the role of germline RUNX1 mutations. Here we show that CDC25C mutations are frequently found in FPD/AML patients (53%). Mutated CDC25C disrupts the G2/M checkpoint and promotes cell cycle progression even in the presence of DNA damage, suggesting a critical role for CDC25C in malignant transformation in FPD/AML. The predicted hierarchical architecture shows that CDC25C mutations define a founding pre-leukaemic clone, followed by stepwise acquisition of subclonal mutations that contribute to leukaemia progression. In three of seven individuals with CDC25C mutations, GATA2 is the target of subsequent mutation. Thus, CDC25C is a novel gene target identified in haematological malignancies. CDC25C is also useful as a clinical biomarker that predicts progression of FPD/AML in the early stage.
Post-transplant lymphoproliferative disorders (PTLDs) are lymphoproliferative diseases that occur after solid organ transplantation or hematopoietic stem cell transplantation (HSCT). The development ...of PTLD is often associated with reactivation of Epstein-Barr virus (EBV). A 26-year-old woman with a history of HSCT and total-body irradiation developed spinal cord hemorrhage from a radiation-induced cavernous hemangioma (RICH) shortly after the development of classical Hodgkin lymphoma PTLD with EBV reactivation. Although little is known about the factors leading to hemorrhagic events from spinal cord RICH, we suspect that EBV reactivation may have been a factor contributing to the hemorrhage in the present case.
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