In this paper, we develop an integral refinement of the Perrin-Riou theory of exponential maps. We also formulate the Perrin-Riou theory for anticyclotomic deformation of modular forms in terms of ...the theory of the Serre–Tate local moduli and interpolate generalized Heegner cycles
p
-adically.
Let
p
be a prime number and let
E
be an elliptic curve defined over ℚ of conductor
N
. Let
K
be an imaginary quadratic field with discriminant prime to
pN
such that all prime factors of
N
split in
K
.... B. Perrin-Riou established the
p
-adic Gross-Zagier formula that relates the first derivative of the
p
-adic
L
-function of
E
over
K
to the
p
-adic height of the Heegner point for
K
when
E
has good
ordinary
reduction at
p
. In this article, we prove the
p
-adic Gross-Zagier formula of
E
for the cyclotomic ℤ
p
-extension at good
supersingular
prime
p
. Our result has an application for the
full
Birch and Swinnerton-Dyer conjecture. Suppose that the analytic rank of
E
over ℚ is 1 and assume that the Iwasawa main conjecture is true for all good primes and the
p
-adic height pairing is not identically equal to zero for all good ordinary primes, then our result implies the full Birch and Swinnerton-Dyer conjecture up to bad primes. In particular, if
E
has complex multiplication and of analytic rank 1, the full Birch and Swinnerton-Dyer conjecture is true up to a power of bad primes and 2.
ACE910 is a recombinant humanized bispecific antibody that binds to activated factor IX and factor X and mimics the cofactor function of factor VIII (FVIII). This first-in-human study examined the ...safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of ACE910 in healthy male adults. A total of 40 Japanese and 24 white subjects were randomized to receive a single subcutaneous injection of ACE910 (Japanese: 0.001, 0.01, 0.1, 0.3, or 1 mg/kg; white: 0.1, 0.3, or 1 mg/kg; n = 6 per dose group) or placebo (n = 2 per dose group). ACE910 exhibited a linear PK profile and had a half-life of ∼4 to 5 weeks. In FVIII-neutralized plasma, ACE910 shortened activated partial thromboplastin time and increased peak height of thrombin generation in a dose-dependent manner. All adverse events were nonserious and did not lead to any subject's withdrawal. Neither clinical findings nor laboratory abnormalities indicating hypercoagulability were observed. Two of 48 subjects receiving ACE910 (1 Japanese and 1 white) were positive for anti-ACE910 antibodies (anti-drug antibodies ADAs). One subject tested positive for ADAs both before and after ACE910 administration, whereas the other became ADA positive after receiving ACE910. The PK and PD profiles of ACE910 were similar in healthy Japanese and white subjects and suggest that ACE910 will be an effective and convenient prophylactic treatment of hemophilia A. This trial was registered at www.clinicaltrials.jp as #JapicCTI-121934.
•Single subcutaneous dosing of ACE910 has a linear PK profile, a half-life of 4 to 5 weeks, and FVIII-mimetic procoagulant activity in humans.•ACE910 at doses up to 1 mg/kg is well tolerated and has no notable adverse hypercoagulable effect in healthy Japanese and white adults.
•BSA improved the enzyme performance and increased product yield of lignocellulose.•BSA reduced un-productive adsorption as well enhanced the enzyme adsorption.•Nutrient supplements, e.g., CSL, ...showed similar effects on enzymatic hydrolysis.•Non-enzymatic protein provided an alternative to intensive pretreatment.
Non-enzymatic proteins were added during hydrolysis of cellulose and simultaneous saccharification and fermentation (SSF) of different biomass materials. Bovine serum albumin (BSA), a model non-enzymatic protein, increased cellulose and xylose conversion efficiency and also enhanced the ethanol yield during SSF of rice straw subjected to varied pretreatments. Corn steep liquor, yeast extract, and peptone also exerted a similar effect as BSA and enhanced the enzymatic hydrolysis of rice straw. Compared to the glucose yields obtained after enzymatic hydrolysis of rice straw in the absence of additives, the glucose yields after 72h of hydrolysis increased by 12.7%, 13.5%, and 13.7% after addition of the corn steep liquor, yeast extract, and peptone, respectively. This study indicated the use of BSA as an alternative to intensive pretreatment of lignocellulosic materials for enhancing enzymatic digestibility. The utilization of non-enzymatic protein additives is promising for application in glucose and ethanol production from lignocellulosic materials.
With the Nobel Prize in Physiology or Medicine in 2018, cancer immunotherapy is attracting more attention than ever before and is strongly expected to develop in the future. Immune checkpoint ...inhibitors were developed as drugs with a completely different mechanism from conventional chemotherapy for cancer patients, and their therapeutic effects were characterized not only by tumor shrinkage but also by long-term survival of cancer patients, which had a strong impact on cancer treatment. On the other hand, as a result of numerous clinical trials, it was found that the efficacy of immune checkpoint inhibitors alone is only about 10-30%. Currently, more than 2,500 clinical trials of combined cancer immunotherapy with immune checkpoint inhibitors are being conducted with the hope of further improving therapeutic efficacy. Another new cancer immunotherapy, Chimeric Antigen Receptor (CAR) gene transfer T-cell therapy, has been approved for B-cell hematopoietic tumors. In this article, we will outline the future prospects of cancer immunotherapy developed in this way, especially from the viewpoint of "strategies for ineffective cancer".
Checkpoint kinase 1 (CHK1) plays a key role in genome surveillance and integrity throughout the cell cycle. Selective inhibitors of CHK1 (CHK1i) are undergoing clinical evaluation for various human ...malignancies, including neuroblastoma. In this study, one CHK1i‐sensitive neuroblastoma cell line, CHP134, was investigated, which characteristically carries MYCN amplification and a chromosome deletion within the 10q region. Among several cancer‐related genes in the chromosome 10q region, mRNA expression of fibroblast growth factor receptor 2 (FGFR2) was altered in CHP134 cells and associated with an unfavorable prognosis of patients with neuroblastoma. Induced expression of FGFR2 in CHP134 cells reactivated downstream MEK/ERK signaling and resulted in cells resistant to CHK1i‐mediated cell growth inhibition. Consistently, the MEK1/2 inhibitor, trametinib, potentiated CHK1 inhibitor–mediated cell death in these cells. These results suggested that FGFR2 loss might be prone to highly effective CHK1i treatment. In conclusion, extreme cellular dependency of ERK activation may imply a possible application for the MEK1/2 inhibitor, either as a single inhibitor or in combination with CHK1i in MYCN‐amplified neuroblastomas.
FGFR2 loss indicated cells that were prone to highly effective CHK1 inhibitor treatment, whereas increased FGFR2 expression implied a possible application for a targeting therapy for MEK/ERK signaling, either as a single inhibitor or in combination with CHK1 inhibitor in neuroblastomas.
Relapsed acute leukemia after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is associated with poor prognosis. In a subset of patients, durable remissions can be achieved with a ...second allo-HSCT (allo-HSCT2). However, many patients experience relapse after allo-HSCT2 and they may be considered for a third allo-HSCT (allo-HSCT3). Nevertheless, the benefit of allo-HSCT3 remains unconfirmed. Thus, herein a retrospective analysis of 253 allo-HSCT3s in patients with relapsed/refractory acute leukemia was carried out. In total, 29 (11.5%) survived at a median follow-up of 794 days (range: 87-4 619). The 3-year leukemia-free survival and overall survival (OS) rates were 9.7% and 10.9%, respectively. Patients who maintained remission for ≥2 years after allo-HSCT2 had a significantly better 3-year OS (35.8%) than those who experienced early relapse (<1 year, 7.8%; 1-2 years, 14.0%; P = 0.004). Complete remission at allo-HSCT3, performance status score of 0-1 at allo-HSCT3, grade I acute graft-versus-host disease after allo-HSCT2, and relapse ≥2 years after allo-HSCT2 were associated with better survival in patients who received allo-HSCT3. The prognosis after allo-HSCT3 in patients with relapsed/refractory acute leukemia is generally unfavorable. However, given the lack of alternative treatment options, allo-HSCT3 may be considered in a group of patients.
Currently, first-line immune checkpoint inhibitors (ICIs), including programmed cell death protein-1 (PD-1) inhibitors, are utilized as monotherapy in advanced non-small cell lung cancer (NSCLC) ...patients with high programmed death ligand-1 (PD-L1) expression (≧50%). Pre-treatment or post-treatment serum soluble PD-L1 (sPD-L1) has been identified as a potential biomarker for assessing ICI efficacy through fixed-point observations. However, existing studies on sPD-L1 changes have produced inconsistent results or have had sample sizes too small to detect clinically meaningful effect sizes. To elucidate the role of sPD-L1, we conducted a collaborative individual patient data meta-analysis of PD-1 inhibitor treatments.
We conducted a thorough search of articles in PubMed via Medline, Embase, Scopus, and Cochrane databases from inception to October 20, 2023. Trials were deemed eligible if they contained individual datasets for advanced NSCLC patients, including data on overall survival (OS)/progression-free survival (PFS), as well as pre- and post-treatment sPD-L1 levels after 3-4 cycles of PD-1 inhibitor treatments. Our analysis focused on patients who completed 3-4 cycles of PD-1 inhibitor treatments. The primary outcome measure was OS/PFS, and we assessed changes in sPD-L1 concentration pre- and post-treatment through ELISA analyses.
From our search, we identified a potential seven trials, encompassing 256 patients. Among these, two trials with 26 patients met the criteria for inclusion in our primary analyses. Over a median follow-up period of 10 months, pooled univariate analysis revealed that increases in sPD-L1 levels during PD-1 inhibitor treatment were not associated with OS (HR = 1.25; CI: 0.52-3.02)/PFS (HR = 1.42; CI: 0.61-3.30) when compared to cases with sPD-L1 decreases. Subgroup analyses indicated that the impact of sPD-L1 changes on overall mortality/progression-related mortality remained consistent regardless of gender, age, or the type of treatment (nivolumab or pembrolizumab).
Our findings suggest that changes in sPD-L1 levels during PD-1 inhibitor treatment do not significantly influence the prognosis of advanced NSCLC patients, regardless of gender, age, or treatment type. Continuous monitoring of sPD-L1 may not offer significant advantages compared to fixed-point observations.
The components of roasted or green coffee beans that promote abdominal fat reduction are not clear. We investigated the effects of daily consumption of coffee enriched in chlorogenic acids (CGA) on ...abdominal fat area in a randomized, double-blind, parallel controlled trial. Healthy, overweight men and women (
= 150, body mass index (BMI) ≥25 to <30 kg/m
) were randomly allocated to high-CGA (369 mg CGA/serving) or control (35 mg CGA/serving) coffee groups. Instant coffee was consumed once daily for 12 weeks, with four-week pre- and post-observation periods. Abdominal fat area and anthropometric measurements were analyzed at baseline and at four, eight, and 12 weeks, and 142 subjects completed the trial. Visceral fat area (VFA), total abdominal fat area (TFA), body weight, and waist circumference significantly decreased in the CGA group compared with the control group, with a group × time interaction (
< 0.001,
= 0.001,
= 0.025, and
= 0.001, respectively). Changes in VFA and TFA from baseline to 12 weeks were significantly greater in the CGA group than in the control group (-9.0 ± 13.9 cm
vs. -1.0 ± 14.3 cm
,
< 0.001; -13.8 ± 22.9 cm
vs. -2.0 ± 16.2 cm
,
< 0.001). No severe adverse events occurred. Consumption of high-CGA coffee for 12 weeks by overweight adults might lower VFA, TFA, BMI, and waist circumference.
The major limitation of cord blood transplantation (CBT) for adults remains the delayed hematopoietic recovery and higher incidence of graft failure, which result in a higher risk of early mortality ...in CBT. We evaluated early overall survival (OS), non‐relapse mortality (NRM), neutrophil engraftment, acute graft‐vs‐host disease, and cause of early death among 9678 adult patients who received single‐unit CBT in Japan between 1998 and 2017. The probability of OS at 100 days was 64.4%, 71.7%, and 78.9% for the periods 1998 to 2007, 2008 to 2012, and 2013 to 2017, respectively (P < .001). The cumulative incidences of NRM at 100 days during the same period were 28.3%, 20.8%, and 14.6%, respectively (P < .001). The cumulative incidences of neutrophil engraftment were also improved during the same period (P < .001). The most common cause of death within 100 days after CBT was bacterial infection in 1998 to 2007 and primary disease in the latter two time periods. Across the three time periods, the proportions of deaths from bacterial and fungal infection, graft failure, hemorrhage, sinusoidal obstructive syndrome, and organ failure decreased in a stepwise fashion. Landmark analysis of OS and NRM after 100 days showed that OS did not change over time in the multivariate analysis. Our registry‐based data demonstrated a significant improvement of early OS after CBT for adults over the past 20 years. The landmark analysis suggested that improvement of early mortality could lead to an improvement of long‐term OS after CBT.
PDF
