In recent years, it has become evident that tumor cells have immune escape mechanisms, and immune checkpoint inhibitor therapy (anti-PD-1/PD-L1 antibody) has shown benefit in various cancers. In ...endometrial tumors with microsatellite-instability (MSI), somatic mutations have the potential to encode ''non-self'' immunogenic antigens, and lymphocytes have been shown to infiltrate the tumor. Therefore, immune checkpoint inhibitor therapy might be effective in endometrial cancers with MSI. Expression of mismatch repair (MMR) proteins (MLH1, PMS2, MSH2, and MSH6), the presence of tumor-infiltrating lymphocytes (CD8+), and PD-1/PD-L1 expression were assessed by immunohistochemistry in 149 patients with endometrial cancer. We examined whether tumors with MSI had an enhanced immune microenvironment and whether MSI could be a predictor of the therapeutic effect of PD-1/PD-L1 immunotherapy in endometrial cancer. Loss of MMR protein expression was identified in 42 (28.2%) of 149 patients (MSI group) with endometrial cancer. There was no significant relationship between MSI status and age (
= 0.193), histological grade (
= 0.097), FIGO stage (
= 0.508), pelvic lymph node metastasis (
= 0.139), or depth of myometrial invasion (
= 0.494). However, the presence of tumor-infiltrating lymphocytes (CD8+) and PD-L1/PD-1 expression were significantly higher in the MSI group compared to the microsatellite-stable group (
= 0.002,
= 0.001, and p = 0.008, respectively). These results suggest that immune checkpoint inhibitors (anti-PD-1/PD-L1 antibody) could be effective in endometrial cancers with MSI. The presence of MSI may be a biomarker for good response to PD-1/PD-L1 immunotherapy in endometrial cancer.
During sickness absence, it appears necessary for psychiatric patients suffering from depression or bipolar disorder to undergo a psychiatric rehabilitation called the rework program that aids in ...work restoration and maintenance. However, few studies have investigated the effects of such a program and predictors of work restoration and maintenance in the participants. Here, we aimed to investigate the effects of a rework program as well as to examine whether cognitive function and mental state at the end of the rework program predict the probability of work restoration and maintenance and whether the frequency of rework program participation predicts successful work restoration and maintenance. The rework program included both patients absent from work and unemployed patients. Patients completed assessments including Trail Making Test Type B (TMT-B), the Wisconsin Card Sorting Test, and the Social Adaptation Self-Evaluation Scale just before graduating from the rework program. Simultaneously, their depressive state was assessed using the Hamilton Depression Rating scale. The patients were divided into the job group, comprising 94 patients who were able to restore their work or get a new job, and the non-job group, comprising 34 patients who were not able to do so. We found that the program was more effective in patients absent from work than in unemployed patients, TMT-B could predict work restoration and maintenance, and the frequency of rework program participation could predict work restoration but not work maintenance. Based on the findings, we propose “Yamashita’s criterion” where a TMT-B completion time of 70 s is the cut-off point for work restoration. The present findings may provide useful evidence that could aid in the further development of rework program(s).
Reducing population dietary salt intake is expected to help prevent cardiovascular disease and thus constrain increasing national healthcare expenditures in Japan’s super-aged society. We aimed to ...estimate the impact of achieving global and national salt-reduction targets (8, <6, and <5 grams/day) on cardiovascular events and national healthcare spending in Japan. Using published data including mean salt intake and systolic blood pressure from the 2019 National Health and Nutrition Survey, we developed a Markov model of a closed cohort of adults aged 40−79 years in 2019 (n = 66,955,000) transitioning among six health states based on the disease course of ischemic heart disease (IHD) and stroke. If mean salt intake were to remain at 2019 levels over 10 years, cumulative incident cases in the cohort would be approximately 2.0 million for IHD and 2.6 million for stroke, costing USD 61.6 billion for IHD and USD 104.6 billion for stroke. Compared with the status quo, reducing mean salt intake towards the targets over 10 years would avert 1−3% of IHD and stroke events and save up to 2% of related national healthcare costs. Attaining dietary salt-reduction goals among adults would yield moderate health economic benefits in Japan.
Rab11 is essential for polarized post-Golgi vesicle trafficking to photosensitive membrane rhabdomeres in
photoreceptors. Here, we found that Parcas (Pcs), recently shown to have guanine nucleotide ...exchange (GEF) activity toward Rab11, co-localizes with Rab11 on the trans-side of Golgi units and post-Golgi vesicles at the base of the rhabdomeres in pupal photoreceptors. Pcs fused with the electron micrography tag APEX2 localizes on 150-300 nm vesicles at the trans-side of Golgi units, which are presumably fly recycling endosomes. Loss of Pcs impairs Rab11 localization on the trans-side of Golgi units and induces the cytoplasmic accumulation of post-Golgi vesicles bearing rhabdomere proteins, as observed in Rab11 deficiency. In contrast, loss of Rab11-specific subunits of the TRAPPII complex, another known Rab11-GEF, does not cause any defects in eye development nor the transport of rhabdomere proteins; however, simultaneous loss of TRAPPII and Pcs results in severe defects in eye development. These results indicate that both TRAPPII and Pcs are required for eye development, but Pcs functions as the predominant Rab11-GEF for post-Golgi transport to photosensitive membrane rhabdomeres.
Abstract
Previous studies have largely failed to clarify the relationship between p16
INK4A
status and cervical adenocarcinoma prognosis. The current study aimed to examine the clinical and ...pathological significance of p16
INK4A
expression in several cervical adenocarcinoma subtypes. Eighty-two samples collected from patients with cervical adenocarcinoma were formalin fixed and paraffin embedded. Next, p16
INK4A
levels were analyzed with immunohistochemistry. Additionally, the relationship between p16
INK4A
expression and clinicopathological factors as well as prognosis was evaluated. The expression of p16
INK4A
was mostly detected in all usual cervical adenocarcinoma subtypes. In the gastric type, only a few cases were positive for p16
INK4A
expression. Results of the Kaplan–Meier analysis indicated that the positive p16
INK4A
expression in tumor cells was significantly associated with favorable progression-free survival and overall survival in patients with cervical adenocarcinoma (
p
= 0.018 and
p
= 0.047, respectively, log-rank test). Our findings suggest that the status of p16
INK4A
expression may influence prognosis. Thus, p16
INK4A
expression could be used as a biomarker for improving the prognosis of patients with cervical adenocarcinoma.
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The acceptance of MEA in Japan is well demand due to its outstanding effectiveness and safety. Infrequently, a repeat MEA or hysterectomy is needed for recurrent menorrhagia in case of failure ...ablation. The reasons of recurrent menorrhagia subsequent MEA treatment are unclear. The objective of current study is to identify the possible causes of menorrhagia repetition following MEA, together with the observation of histological changes in the endometrium due to this treatment compared with normal cycling endometrial tissue. A total of 170 patients, 8 (4.7%) of them carried out hysterectomy after 16.8 months (range, 2-29 months) of MEA treatment. Normal (n = 47) and MEA (n = 8) treated paraffin embedded endometrial tissue were prepared for hematoxylin and eosin (H&E) and immunostaining study to recognize the histological changes in the endometrium as a result of MEA treatment. The histological features observed increased tubal metaplasia (TM) including negative expression of the estrogen receptor (ER) and progesterone receptor (PR) in the endometrium subsequent MEA treatment. Increased TM together with the absence of ER and PR expression might be a reasonable explanation for repetition menorrhagia in cases of failure ablation. Further study is required to clarify the molecular mechanisms of tubal metaplasia and the expression loss of hormone receptor in the endometrium as a result of MEA treatment. Current studies propose that low dose estrogen-progestin may not be effective with recurrent menorrhagia patient's due to the inadequacy of hormone receptor expression in the endometrium following MEA.
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The survival of patients with advanced or recurrent ovarian cancer has improved tremendously in the past decade, mainly due to the establishment of maintenance therapy with poly (ADP-ribose) ...polymerase (PARP) inhibitors (PARPis) after conservative chemotherapies. Despite their superior efficacy, resistance to PARPis has been reported, and patients with resistance have a much worse prognosis. Therefore, the development of novel treatment strategies to overcome PARPi resistance is urgently needed. The present review article focuses on the molecular mechanisms of how PARPis exert cytotoxic effects on cancer cells through DNA repair processes, especially the genetic background and tumor microenvironment favored by PARPis. Furthermore, currently available information on PARPi resistance mechanisms is introduced and discussed to develop a novel therapeutic approach against them.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Dedifferentiated endometrial carcinoma (DDEC) is defined as an undifferentiated carcinoma admixed with differentiated endometrioid carcinoma (Grade 1 or 2). It has poor prognosis compared with Grade ...3 endometrioid adenocarcinoma and is often associated with the loss of mismatch repair (MMR) proteins, which is seen in microsatellite instability (MSI)-type endometrial cancer. Recent studies have shown that the effectiveness of immune checkpoint inhibitor therapy is related to MMR deficiency; therefore, we analyzed the immunophenotype (MMR deficient and expression of PD-L1) of 17 DDEC cases. In the undifferentiated component, nine cases (53%) were deficient in MMR proteins and nine cases (53%) expressed PD-L1. PD-L1 expression was significantly associated with MMR deficiency (
= 0.026). In addition, the presence of tumor-infiltrating lymphocytes (CD8+) was significantly associated with MMR deficiency (
= 0.026). In contrast, none of the cases showed PD-L1 expression in the well-differentiated component. Our results show that DDEC could be a target for immune checkpoint inhibitors (anti PD-L1/PD-1 antibodies), especially in the undifferentiated component. As a treatment strategy for DDEC, conventional paclitaxel plus carboplatin and cisplatin plus doxorubicin therapies are effective for those with the well-differentiated component. However, by using immune checkpoint inhibitors in combination with other conventional treatments, it may be possible to control the undifferentiated component and improve prognosis.
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Background: AT-rich interaction domain 1A (ARID1A) has been proposed as a new biomarker for predicting response to immune checkpoint inhibitors (ICIs). The predictive value of ARID1A for predicting ...ICI effectiveness has not been reported for endometrial cancer. Therefore, we investigated whether ARID1A negativity predicts ICI effectiveness for endometrial cancer treatment. Methods: We evaluated ARID1A expression, tumor-infiltrating lymphocytes (CD8+), and immune checkpoint molecules (PD-L1/PD-1) by immunostaining endometrial samples from patients with endometrial cancer. Samples in which any of the four mismatch repair proteins (MLH1, MSH2, MSH6, and PMS2) were determined to be negative via immunostaining were excluded. In the ARID1A-negative group, microsatellite instability (MSI) status was confirmed via MSI analysis. Results: Of the 102 samples investigated, 25 (24.5%) were ARID1A-negative. CD8 and PD-1 expression did not differ significantly between the ARID1A-negative group and the ARID1A-positive group; however, the ARID1A-negative group showed significantly lower PD-L1 expression. Only three samples (14.2%) in the ARID1A-negative group showed high MSI. Sanger sequencing detected three cases of pathological mutation in the MSH2-binding regions. We also established an ARID1A-knockout human ovarian endometriotic epithelial cell line (HMOsisEC7 ARID1A KO), which remained microsatellite-stable after passage. Conclusion: ARID1A negativity is not suitable as a biomarker for ICI effectiveness in treating endometrial cancer.
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Objective
Reducing dietary salt intake is an essential population strategy for cardiovascular disease (CVD) prevention, but evidence on healthcare costs and outcomes is limited in Japan. We aimed to ...conduct a pilot economic evaluation under hypothetical scenarios of applying the salt reduction policies of England to Japan.
Methods
We examined salt reduction policies in England: media health promotion campaigns, front-of-pack labeling, and voluntary and mandatory reformulation with best-case and worst-case policy cost scenarios. We assumed that these policies were conducted in Japan for 10 years from 2019. We used published data on epidemiology and healthcare expenditures in Japan and the costs and effects of salt reduction policies in England, and defined the benefits as a decrease in national medical expenditures on CVD. We developed a Markov cohort simulation model of the Japanese population. To estimate the annual net benefits of each policy over 10 years, we subtracted monitoring and policy costs from the benefits. We adopted a health sector perspective and a 2% discount rate.
Results
The cumulative net benefit over 10 years was largest for mandatory reformulation (best case) at 2,015.1 million USD (with costs of USD 48.3 million and benefits of USD 2063.5 million), followed by voluntary reformulation (net benefit: USD 1,895.1 million, cost: USD 48.1 million, benefit: USD 1,943.2 million), mandatory reformulation (worst case, net benefit: USD 1,447.9 million, cost: USD 1,174.5 million, benefit: USD 2,622.3 million), labeling (net benefit: USD 159.5 million, cost: USD 91.6 million, benefit: USD 251.0 million), and a media campaign (net benefit: USD 140.5 million, cost: USD 110.5 million, benefit: USD 251.0 million). There was no change in the superiority or inferiority of policies when the uncertainty of model parameters was considered.
Conclusion
Mandatory reformulation with the best-case cost scenario might be economically preferable to the other alternatives in Japan. In future research, domestic data on costs and effects of salt reduction policies should be incorporated for model refinement.
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