Chondroitin sulfate proteoglycan 4: An attractive target for antibody-based immunotherapy.

Multifunctional molecules involved in tumor progression and metastasis have been identified as valuable targets for immunotherapy. Among these, chondroitin sulfate proteoglycan 4 (CSPG4), a significant tumor cell membrane-bound proteoglycan, has emerged as a promising target, especially in light of advances in chimeric antigen receptor (CAR) T-cell therapy. The profound bioactivity of CSPG4 and its role in pivotal processes such as tumor proliferation, migration, and neoangiogenesis underline its therapeutic potential. We reviewed the molecular intricacies of CSPG4, its functional attributes within tumor cells, and the latest clinical-translational advances targeting it. Strategies such as blocking monoclonal antibodies, conjugate therapies, bispecific antibodies, small-molecule inhibitors, CAR T-cell therapies, trispecific killer engagers, and ribonucleic acid vaccines against CSPG4 were assessed. CSPG4 overexpression in diverse tumors and its correlation with adverse prognostic outcomes emphasize its significance in cancer biology. These findings suggest that targeting CSPG4 offers a promising avenue for future cancer therapy, with potential synergistic effects when combined with existing treatments.

Pneumocystis Pneumonia in Locally Advanced Breast Cancer Despite Prophylactic Use of Trimethoprim-Sulfamethoxazole During Prednisolone Treatment for a Pembrolizumab-Induced Immune-Related Adverse Event: A Case Report.

Pneumocystis pneumonia (PCP) primarily affects immunosuppressed patients, with trimethoprim-sulfamethoxazole (TMP-SMX) commonly used for prophylaxis. However, there is insufficient information on PCP occurrence despite TMP-SMX prophylaxis. We encountered a 57-year-old woman with locally advanced breast cancer developing PCP despite prophylactic intake of TMP-SMX, during treatment with prednisolone for Stevens-Johnson syndrome (SJS) induced by pembrolizumab. This case underscores the need to pay attention to the possibility of PCP development even during TMP-SMX prophylaxis. Dosage and duration adjustments according to the patient's condition and weight may be required.

Multicenter prospective randomized controlled clinical trial comparing the pocket-creation method with and without single-clip traction of colonic endoscopic submucosal dissection.

BACKGROUND: The pocket-creation method (PCM) was developed to overcome the technical difficulties of endoscopic submucosal dissection (ESD), although opening the pocket remains challenging. We developed a novel technique of PCM with single-clip traction (PCM-CT), which uses a reopenable clip as a traction device to maintain stability during the procedure. No prospective study has compared the efficacy of PCM-CT and PCM. This study aimed to investigate the effectiveness of PCM-CT vs. PCM in a randomized controlled trial. METHODS: This randomized controlled clinical trial was conducted at four Japanese institutions. Patients with superficial colorectal neoplastic lesions were included following Japanese guidelines for colorectal cancer. Seven moderately experienced endoscopists performed the ESD procedures using either PCM-CT or PCM. RESULTS: 100 patients were enrolled in the study. Compared with PCM, PCM-CT achieved significantly faster mean (SD) dissection speed (21.4 [10.8] vs. 27.0 [14.5] mm2/min [95%CI 0.5 to 10.7], P = 0.03), and reduced the mean procedure time (81.8 [57.9] vs. 64.8 [47.6] minutes [95%CI -38.2 to 4.3], P = 0.12) and pocket-opening time (37.8 [33.0] vs. 30.0 [28.9] minutes [95%CI -20.2 to 4.6], P = 0.22). En bloc and R0 resection rates were not significantly different between the two groups (100% vs. 100%, P >0.99; 100% vs. 96%, P = 0.50, respectively). No significant differences were observed in adverse events between the two groups. CONCLUSION: ESD facilitated by the novel PCM-CT method appeared to be significantly faster than PCM. Both methods achieved high R0 resection rates.

Long-term Experience on Breast Cancer-related Lymphedema in the Coastal Area of Fukushima, Japan After the 2011 Triple Disaster.

BACKGROUND/AIM: Disasters can jeopardize breast cancer care and Japan's triple disaster in 2011 (earthquake, tsunami, and nuclear accident) is no exception. However, detailed information is lacking regarding the care of breast cancer related lymphedema (BCRL) following the disaster. We aimed to explore the process by which local patients become aware of BCRL, the problems faced, and the support they require. We also aimed to clarify the effects of the 2011 disaster on experiences related to lymphedema in the target population. PATIENTS AND METHODS: Patients who developed BCRL after breast cancer treatment were recruited from Iwaki city, a municipality located in the southern coastal region of Fukushima (N=16). In-depth, semi-structured, face-to-face interviews were conducted, and the obtained data were appraised using thematic analysis. RESULTS: Five themes related to BCRL were identified: 1) the process of becoming aware of BCRL, 2) troubles or worries/concerns due to BCRL, 3) information sources regarding BCRL management, 4) strategies to cope with BCRL, and 5) the adverse impacts of the 2011 disaster on BCRL management. CONCLUSION: Except for the disaster context, the themes are in line with those of previous studies conducted in the non-disaster context. Nonetheless, there were limited but non-negligible adverse effects of the 2011 disaster on long-term local BCRL management. The findings of this study demonstrate the necessity for individualizing coping strategies against BCRL among healthcare professionals in the Fukushima coastal area and beyond.

Differential gene regulation by a synthetic vitamin D receptor ligand and active vitamin D in human cells.

Vitamin D (VD) exerts a wide variety of biological functions including calcemic activity. VD nutritional status is closely associated with the onset and development of chronic diseases. To develop a VD analog with the desired VD activity but without calcemic activity, we screened synthetic VDR antagonists. We identified 1α,25-dihydroxyvitamin D3-26-23-lactams (DLAM)-2a-d (DLAM-2s) as nuclear vitamin D receptor (VDR) ligands in a competitive VDR binding assay for 1α,25(OH)2 vitamin D3 (1α,25(OH)2D3), and DLAM-2s showed an antagonistic effect on 1α,25(OH)2 D3-induced cell differentiation in HL60 cells. In a luciferase reporter assay in which human VDR was exogenously expressed in cultured COS-1 cells, DLAM-2s acted as transcriptional antagonists. Consistently, DLAM-2s had an antagonistic effect on the 1α,25(OH)2D3-induced expression of a known VD target gene [Cytochrome P450 24A1 (CYP24A1)], and VDR bound DLAM-2s was recruited to an endogenous VD response element in chromatin in human keratinocytes (HaCaT cells) endogenously expressing VDR. In an ATAC-seq assay, the effects of 1α,25(OH)2 D3 and DLAM-2b on chromatin reorganization were undetectable in HaCaT cells, while the effect of an androgen receptor (AR) antagonist (bicalutamide) was confirmed in prostate cancer cells (LNCaP) expressing endogenous AR. However, whole genome analysis using RNA-seq and ATAC (Assay for Transposase Accessible Chromatin)-seq revealed differential gene expression profiles regulated by DLAM-2b versus 1α,25(OH)2D3. The upregulated and downregulated genes only partially overlapped between cells treated with 1α,25(OH)2D3 and those treated with DLAM-2b. Thus, the present findings illustrate a novel VDR ligand with gene regulatory activity differing from that of 1α,25(OH)2D3.

Telepathology in intraoperative frozen section consultation of breast cancer sentinel node biopsy in Fukushima, Japan following the 2011 triple disaster: diagnostic accuracy and required time during the early implementation phase.

In breast cancer surgery, some medical facilities lack the necessary resources to conduct sentinel lymph node biopsy and its intraoperative frozen section consultation. In the coastal rural area of Fukushima, Japan, which has suffered from physician undersupply following the 2011 triple disaster of earthquake, tsunami and nuclear disaster, we explored the feasibility of telepathology by evaluating the diagnostic accuracy in remote intraoperative frozen section consultation of sentinel lymph node biopsy and its required time. Although examination time has room for improvement, telepathology can be one possible solution in resource-limited areas.

Advances in the Administration of Vitamin D Analogues to Support Bone Health and Treat Chronic Diseases.

Vitamin D (VD) exerts a wide variety of biological actions in addition to its well-known roles in calcium homeostasis. Nutritional VD deficiency induces rachitic abnormalities in growing children and osteomalacia in adults, and it has been proposed to underlie the onset and development of multiple non-communicable chronic diseases. Therefore, the administration of VD or synthetic VD analogues represents a promising therapeutic strategy; indeed, VD and a VD agonist have shown clinical promise in mitigating osteoporosis and symptoms of insufficient calcium intake. However, even though high doses of VD analogues have shown pre-clinical efficacy against several diseases, including cancers, they have not yet had wide-spread clinical success. This difference may be due to limitation of clinical doses in light of the inherent calcemic action of VD. An approach to overcome this problem involves the development of VD analogues with lower calcemic activity, which could be administered in high doses to attenuate the onset and progress of disease. In a similar strategy, selective estrogen receptor modulators have had success as anti-osteoporosis drugs, and they have shown benefit for other estrogen target organs by serving as partial antagonists or agonists of estrogen receptor α. It is thus conceivable to generate synthetic partial antagonists or agonists for the VD receptor (VDR) that would exert beneficial effects on bone and other VD target organs. In this review, we discuss the molecular basis of the development of such synthetic VDR ligands from the viewpoint of roles of VDR in gene regulation.

The necessity of proactive measures from healthcare providers highlighted by delayed breast cancer diagnosis due to COVID-19: A case report.

Key Clinical Message: During disasters, multiple factors can cause significant delays in medical visits. Regular patient monitoring, high-risk individual alerts, and telemedicine enhancements can potentially alleviate these issues and ensure timely interventions. Abstract: During the COVID-19 pandemic, a Japanese woman in her 70s delayed her regular breast cancer checkup for over 2 years. During disasters, health priorities tend to decline, necessitating proactive measures from healthcare providers, such as augmenting collaboration among healthcare professionals and identifying high-risk individuals.

The epigenetic function of androgen receptor in prostate cancer progression.

Androgen and androgen deprivation (castration) therapies, including androgen receptor antagonists, are clinically used to treat patients with prostate cancer. However, most hormone-dependent prostate cancer patients progress into a malignant state with loss of hormone-dependency, known as castration (drug)-resistant prostate cancer (CRPC), after prolong androgen-based treatments. Even in the CRPC state with irreversible malignancy, androgen receptor (AR) expression is detectable. An epigenetic transition to CRPC induced by the action of AR-mediated androgen could be speculated in the patients with prostate cancer. Androgen receptors belongs to the nuclear receptor superfamily with 48 members in humans, and acts as a ligand-dependent transcriptional factor, leading to local chromatin reorganization for ligand-dependent gene regulation. In this review, we discussed the transcriptional/epigenetic regulatory functions of AR, with emphasis on the clinical applications of AR ligands, AR protein co-regulators, and AR RNA coregulator (enhancer RNA), especially in chromatin reorganization, in patients with prostate cancer.

Duration and Influencing Factors of Postoperative Urinary Incontinence after Robot-Assisted Radical Prostatectomy in a Japanese Community Hospital: A Single-Center Retrospective Cohort Study.

OBJECTIVES: Post-operative urinary incontinence (PUI) after robotic-assisted radical prostatectomy (RARP) is an important complication; PUI occurs immediately after postoperative urethral catheter removal, and, although approximately 90% of patients improve within one year after surgery, it can significantly worsen their quality of life. However, information is lacking on its nature in community hospital settings, particularly in Asian countries. The purposes of this study were to investigate the time required to recover from PUI after RARP and to identify its associated factors in a Japanese community hospital. METHODS: Data were extracted from the medical records of 214 men with prostate cancer who underwent RARP from 2019 to 2021. We then calculated the number of days elapsed from the surgery to the initial outpatient visit confirming PUI recovery among the patients. We estimated the PUI recovery rate using the Kaplan-Meier product limit method and evaluated associated factors using the multivariable Cox proportional hazards model. RESULTS: The PUI recovery rates were 5.7%, 23.4%, 64.6%, and 93.3% at 30, 90, 180, and 365 days following RARP, respectively. After an adjustment, those with preoperative urinary incontinence experienced significantly slower PUI recovery than their counterparts, while those with bilateral nerve sparing experienced recovery significantly sooner than those with no nerve sparing. CONCLUSION: Most PUI improved within one year, but a proportion of those experiencing recovery before 90 days was smaller than previously reported.

Why only me? A case report of a breast cancer patient with unresolved trauma from a past disaster experience developing a mental disorder.

Little is known about how the psychological stress of having experienced a natural disaster affects cancer patients. We experienced a patient who was treated with breast cancer after having been stricken by a typhoon, which resulted in significant psychological damage. Treatment strategies should incorporate patients' mental health appropriately after disasters.

Association between COVID-19 incidence and postponement or cancellation of elective surgeries in Japan until September 2020: a cross-sectional, web-based survey.

OBJECTIVES: This study aimed to examine whether and how the COVID-19 pandemic has affected the postponement or cancellation of elective surgeries in Japan. DESIGN AND SETTING: A cross-sectional, web-based, self-administered survey was conducted nationwide from August 25 to September 30 2020. We used data from the Japan 'COVID-19 and Society' Internet Survey collected by a large internet research agency, Rakuten Insight, which had approximately 2.2 million qualified panellists in 2019. PARTICIPANTS: From a volunteer sample of 28 000 participants, we extracted data from 3678 participants with planned elective surgeries on any postponement or cancellation of elective surgeries. OUTCOME MEASURES: The main outcome measure was any postponement or cancelltion of elective surgeries. In addition, for all respondents, we extracted data on sociodemographic, health-related characteristics, psychological characteristics and prefectural-level residential areas. We used weighted logistic regression approaches to fulfil the study objectives, minimising potential bias relating to web-based surveys. RESULTS: Of the 3678 participants, 431 (11.72%) reported experiencing postponement or cancellation of their elective surgeries. Notably, the participants living in prefectures where the declaration of the state of emergency was made on 7 April 2020 were significantly more likely to experience postponement or cancellation of elective surgeries than those residing in prefectures with the state of emergency beginning on 16 April 2020 (174 (26.02%) vs 153 (12.15%)). CONCLUSIONS: The proportion of patients whose elective surgery had been postponed was limited during Japan's first wave of the COVID-19 pandemic, although the declaration of a state of emergency increased the likelihood of postponement. It is imperative to increase awareness of the secondary health effects related to policy intervention in pandemics and other health crises and to use appropriate countermeasures such as standard infectious control measures and triage of surgical patients.

Interruption of breast cancer care and importance of inter-hospital cooperation during the COVID-19 pandemic: A case report of advanced breast cancer in Fukushima, Japan.

We experienced the case of a patient with advanced breast cancer who failed to receive comprehensive care despite regular video conferencing with her physician during the COVID-19 pandemic, resulting in delayed detection of liver metastasis. Inter-hospital collaboration is required to provide uninterrupted cancer care to those disproportionately affected by crises.

Colorectal Cancer Screening Program in Songjiang district, Shanghai between 2015 and 2017: Evaluation of participation rate and the associated factor.

Little is known about the participation rate of newly implemented colorectal cancer (CRC) screening programs in China. Our goals were to identify factors associated with nonparticipation for CRC screening in Songjiang District, Shanghai. We analyzed individuals included in an observational cohort study from 4 towns (Xin Qiao, She Shan, Mao Gang, and Zhong Shan) in Songjiang District. The participation rate was calculated for the CRC screening program based on a fecal immunochemical test and a risk assessment questionnaire between 2015 and 2017 inclusive. Of the 27,130 individuals eligible for inclusion in this study, 20,863 (76.9%) participated in CRC screening at least once during 2015 and 2017. The factors linked with nonparticipation were; being male (odds ratio [OR] 0.87, 95% confidence interval [CI] 0.82-0.93, P < .01), unmarried (OR 0.71, 95% CI 0.64-0.80, P < .01), having a high education level (middle school, OR 0.82, 95% CI 0.74-0.90, P < .01, high school or above, OR 0.64, 95% CI 0.57-0.73, P < .01), absence of chronic disease (OR 0.90, 95% CI 0.85-0.96, P < .01), and living in 2 out of the 4 towns covered (Xin Qiao, OR 0.72, 95% CI 0.66-0.78, P < .01, Zhong Shan, OR 0.29, 95% CI 0.26-0.31, P < .01). The current study revealed several associated factors with nonparticipation for the CRC screening in Songjiang district. These findings will help identify target populations that require an individualized approach to increase the participation rate.

Strangulated transomental hernia in virgin abdomen: laparoscopic surgery with a small laparotomy may be useful to assess the indeterminate viability of the bowel.

A 66-year-old female without prior history of abdominal surgery visited the emergency department with a complain of sudden intensive lower abdominal pain. Closed loop bowel obstruction was discovered on contrast-enhanced computed tomography, leading to a laparoscopic examination of 5 h after the onset. During laparoscopy, 100 cm of distal jejunum with borderline viability was found incarcerated in a gap of the greater omentum. A 3-cm small incision was made at the umbilical trocar site to observe the bowel after it was released laparoscopically. When viewed under the shadowless lamp, the affected bowel appeared reddish, with peristalsis and a palpated mesentery artery. The surgical team determined no need for resection. The postoperative recovery went smoothly without any complications. Laparoscopic surgery for transomental hernias can be performed safely even in patients with borderline bowel viability, and observing bowel extra-peritoneally with a small incision could be helpful for laparoscopic surgery for internal hernias with borderline viability.

Identification of cell cycle-associated and -unassociated regulators for expression of a hepatocellular carcinoma oncogene cyclin-dependent kinase inhibitor 3.

Human cyclin-dependent kinase inhibitor 3 (CDKN3) is a known oncogene in hepatocellular carcinoma (HCC) and its expression is promoted during tumor development. CDKN3 serves as a cell cycle regulator and its dysregulation is considered to be a causal factor for tumor progression. However, the molecular basis of the regulation of CDKN3 expression remains largely elusive. Using in silico approach, we identified CDKN3SE, a super enhancer (SE), and enhancer RNA (eRNA) candidates transcribed from this SE. Among the eRNA candidates, the expression of CDKN3eRNA was detected in the human HCC model cell line HepG2, and was found to facilitate the expression of CDKN3 without affecting the cell proliferation rate. In silico screening revealed two DNA-binding transcription factors, upstream stimulatory factor (USF) 1 and 2, involved in the regulation of CDKN3eRNA expression on CDKN3SE. A knock-down of USF1/USF2 expression in the HepG2 cells did not affect CDKN3eRNA expression, while the expression of CDKN3 was down-regulated. In a USF2 dominant negative HepG2 cell line generated by genome editing, a drastically altered cell shape and lowered cell proliferation rate were found; however, the expression of CDKN3eRNA appeared unaffected. Thus, the present study illustrated two regulators for CDKN3 expression: USF2, as a cell cycle-associated protein regulator, and CDKN3eRNA, as a cell cycle-unassociated RNA regulator.

A long non-coding RNA as a direct vitamin D target transcribed from the antisense strand of the human HSD17B2 locus.

Vitamin D (VD) exerts a wide variety of actions via gene regulation mediated by the nuclear vitamin D receptor (VDR) under physiological and pathological settings. However, the known target genes of VDR appear unlikely to account for all VD actions. We used in silico and transcriptomic approaches in human cell lines to search for non-coding RNAs transcriptionally regulated by VD directly. Four long non-coding RNAs (lncRNAs), but no microRNAs (miRNAs), were found, supported by the presence of consensus VDR-binding motifs in the coding regions. One of these lncRNAs (AS-HSD17ß2) is transcribed from the antisense strand of the HSD17ß2 locus, which is also a direct VD target. AS-HSD17ß2 attenuated HSD17ß2 expression. Thus, AS-HSD17ß2 represents a direct lncRNA target of VD.

Antagonistic action of a synthetic androgen ligand mediated by chromatin remodeling in a human prostate cancer cell line.

The clinical use of androgen receptor (AR) antagonists has been successful in treating prostate cancer patients, inducing remission of androgen-dependent tumors. However, a couple of years after treatment, prostate tumors transition into an androgen-independent state with altered gene expression profiles, but the molecular basis is not understood. Since the AR antagonists trigger this transition, we assessed whether AR antagonists induce chromatin reorganization in an androgen-dependent prostate cancer cell line (LNCaP). Treatment of LNCaP cells with two clinically used AR antagonists (bicalutamide [Bic] and enzalutamide [Enz]) expectedly resulted in antagonistic effects on cell proliferation, AR transactivation, and dihydrotestosterone (DHT)-induced expression of AR target genes. Thus, the antagonists expectedly acted to antagonize the transactivation function of AR activated by androgen binding. By ChIP-qPCR assay, AR bound to Bic, but not Enz, was recruited to an endogenous consensus AR-binding site within the kallikrein-related peptidase 3 gene promoter after treatment with Bic, similar to the effect of DHT. By ATAC-seq analysis of the cells after long-term treatment for 5 days, Bic and dihydrotestosterone DHT induced different chromatin reorganization patterns and gene expression profiles, suggesting that Bic exhibited a distinct action from that by DHT. Thus, these results suggest that the action of a known AR antagonist is mediated by chromatin reorganization in a prostate cancer cell line.