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Aging Jun 2024Lung adenocarcinoma (LUAD) is a prevalent malignant tumor worldwide, with high incidence and mortality rates. However, there is still a lack of specific and sensitive...
PURPOSE
Lung adenocarcinoma (LUAD) is a prevalent malignant tumor worldwide, with high incidence and mortality rates. However, there is still a lack of specific and sensitive biomarkers for its early diagnosis and targeted treatment. Disulfidptosis is a newly identified mode of cell death that is characteristic of disulfide stress. Therefore, exploring the correlation between disulfidptosis-related long non-coding RNAs (DRGs-lncRNAs) and patient prognosis can provide new molecular targets for LUAD patients.
METHODS
The study analysed the transcriptome data and clinical data of LUAD patients in The Cancer Genome Atlas (TCGA) database, gene co-expression, and univariate Cox regression methods were used to screen for DRGs-lncRNAs related to prognosis. The risk score model of lncRNA was established by univariate and multivariate Cox regression models. TIMER, CIBERSORT, CIBERSORT-ABS, and other methods were used to analyze immune infiltration and further evaluate immune function analysis, immune checkpoints, and drug sensitivity. Real-time polymerase chain reaction (RT-PCR) was performed to detect the expression of DRGs-lncRNAs in LUAD cell lines.
RESULTS
A total of 108 lncRNAs significantly associated with disulfidptosis were identified. A prognostic model was constructed by screening 10 lncRNAs with independent prognostic significance through single-factor Cox regression analysis, LASSO regression analysis, and multiple-factor Cox regression analysis. Survival analysis of patients through the prognostic model showed that there were obvious survival differences between the high- and low-risk groups. The risk score of the prognostic model can be used as an independent prognostic factor independent of other clinical traits, and the risk score increases with stage. Further analysis showed that the prognostic model was also different from tumor immune cell infiltration, immune function, and immune checkpoint genes in the high- and low-risk groups. Chemotherapy drug susceptibility analysis showed that high-risk patients were more sensitive to Paclitaxel, 5-Fluorouracil, Gefitinib, Docetaxel, Cytarabine, and Cisplatin. Additionally, RT-PCR analysis demonstrated differential expression of DRGs-lncRNAs between LUAD cell lines and the human bronchial epithelial cell line.
CONCLUSIONS
The prognostic model of DRGs-lncRNAs constructed in this study has certain accuracy and reliability in predicting the survival prognosis of LUAD patients, and provides clues for the interaction between disulfidptosis and LUAD immunotherapy.
Topics: Humans; RNA, Long Noncoding; Adenocarcinoma of Lung; Lung Neoplasms; Prognosis; Biomarkers, Tumor; Gene Expression Regulation, Neoplastic; Immunotherapy; Male; Female; Cell Line, Tumor; Transcriptome; Middle Aged
PubMed: 38862217
DOI: 10.18632/aging.205911 -
Cell & Bioscience Jun 2024Paraptosis is a programmed cell death characterized by cytoplasmic vacuolation, which has been explored as an alternative method for cancer treatment and is associated...
BACKGROUND
Paraptosis is a programmed cell death characterized by cytoplasmic vacuolation, which has been explored as an alternative method for cancer treatment and is associated with cancer resistance. However, the mechanisms underlying the progression of paraptosis in cancer cells remain largely unknown.
METHODS
Paraptosis-inducing agents, CPYPP, cyclosporin A, and curcumin, were utilized to investigate the underlying mechanism of paraptosis. Next-generation sequencing and liquid chromatography-mass spectrometry analysis revealed significant changes in gene and protein expressions. Pharmacological and genetic approaches were employed to elucidate the transcriptional events related to paraptosis. Xenograft mouse models were employed to evaluate the potential of paraptosis as an anti-cancer strategy.
RESULTS
CPYPP, cyclosporin A, and curcumin induced cytoplasmic vacuolization and triggered paraptosis in cancer cells. The paraptotic program involved reactive oxygen species (ROS) provocation and the activation of proteostatic dynamics, leading to transcriptional activation associated with redox homeostasis and proteostasis. Both pharmacological and genetic approaches suggested that cyclin-dependent kinase (CDK) 7/9 drive paraptotic progression in a mutually-dependent manner with heat shock proteins (HSPs). Proteostatic stress, such as accumulated cysteine-thiols, HSPs, ubiquitin-proteasome system, endoplasmic reticulum stress, and unfolded protein response, as well as ROS provocation primarily within the nucleus, enforced CDK7/CDK9-Rpb1 (RNAPII subunit B1) activation by potentiating its interaction with HSPs and protein kinase R in a forward loop, amplifying transcriptional regulation and thereby exacerbating proteotoxicity leading to initiate paraptosis. The xenograft mouse models of MDA-MB-231 breast cancer and docetaxel-resistant OECM-1 head and neck cancer cells further confirmed the induction of paraptosis against tumor growth.
CONCLUSIONS
We propose a novel regulatory paradigm in which the activation of CDK7/CDK9-Rpb1 by nuclear proteostatic stress mediates transcriptional regulation to prime cancer cell paraptosis.
PubMed: 38858714
DOI: 10.1186/s13578-024-01260-2 -
International Journal of Surgery Case... Jul 2024Radiation recall dermatitis (RRD) is a localized drug-induced inflammatory skin reaction occurring exclusively in a previously irradiated site months to years after...
INTRODUCTION AND IMPORTANCE
Radiation recall dermatitis (RRD) is a localized drug-induced inflammatory skin reaction occurring exclusively in a previously irradiated site months to years after discontinuation of ionizing radiation. The symptoms of RRD can range from mild redness to extensive dermatitis. Antineoplastic drugs such as doxorubicin, docetaxel, paclitaxel, and gemcitabine are most commonly associated with radiation recall reactions. These reactions can also occur with antibiotics and anti-tubercular drugs.
CASE PRESENTATION
A 38-years-old woman with hormone receptor-negative, HER2-positive inflammatory breast cancer (right), clinical stage cT4dN1Mx, received neoadjuvant chemotherapy with AC > TH protocol at 3 weeks intervals (Anthracycline-Doxorubicin plus Cyclophosphamide X 4 cycles, then docetaxel plus Trastuzumab X 4 cycles) followed by modified radical mastectomy followed by adjuvant locoregional radiotherapy. She received the 5th cycle and 6th cycle trastuzumab monotherapy just before the start of surgery and radiotherapy, respectively. After 1 month of completion of radiotherapy, during her seventh cycle of Trastuzumab monotherapy, she developed mild edema with erythematous change over the previously irradiated area with fever. A skin biopsy was taken to exclude any recurrence; however, no evidence of malignancy was found.
CLINICAL DISCUSSION
We diagnosed it as a case of RRD. We managed her conservatively. Later, she was rechallenged with the same dose in subsequent cycles with systemic steroid coverage, which she tolerated very well, except for the reappearance of mild erythema following each cycle of maintenance dose of Trastuzumab.
CONCLUSION
Radiation recall dermatitis is an extremely rare phenomenon; hence, an acquaintance of clinicians with this rare entity is essential for timely diagnosis and appropriate management.
PubMed: 38852571
DOI: 10.1016/j.ijscr.2024.109864 -
International Journal of Nanomedicine 2024The commercial docetaxel (DTX) formulation causes severe side effects due to polysorbate 80 and ethanol. Novel surfactant-free nanoparticle (NP) systems are needed to...
Crafting Docetaxel-Loaded Albumin Nanoparticles Through a Novel Thermal-Driven Self-Assembly/Microfluidic Combination Technology: Formulation, Process Optimization, Stability, and Bioavailability.
BACKGROUND
The commercial docetaxel (DTX) formulation causes severe side effects due to polysorbate 80 and ethanol. Novel surfactant-free nanoparticle (NP) systems are needed to improve bioavailability and reduce side effects. However, controlling the particle size and stability of NPs and improving the batch-to-batch variation are the major challenges.
METHODS
DTX-loaded bovine serum albumin nanoparticles (DTX-BSA-NPs) were prepared by a novel thermal-driven self-assembly/microfluidic technology. Single-factor analysis and orthogonal test were conducted to obtain the optimal formulation of DTX-BSA-NPs in terms of particle size, encapsulation efficiency (EE), and drug loading (DL). The effects of oil/water flow rate and pump pressure on the particle size, EE, and DL were investigated to optimize the preparation process of DTX-BSA-NPs. The drug release, physicochemical properties, stability, and pharmacokinetics of NPs were evaluated.
RESULTS
The optimized DTX-BSA-NPs were uniform, with a particle size of 118.30 nm, EE of 89.04%, and DL of 8.27%. They showed a sustained release of 70% over 96 hours and an increased stability. There were some interactions between the drug and excipients in DTX-BSA-NPs. The half-life, mean residence time, and area under the curve (AUC) of DTX-BSA-NPs increased, but plasma clearance decreased when compared with DTX.
CONCLUSION
The thermal-driven self-assembly/microfluidic combination method effectively produces BSA-based NPs that improve the bioavailability and stability of DTX, offering a promising alternative to traditional formulations.
Topics: Docetaxel; Animals; Serum Albumin, Bovine; Nanoparticles; Biological Availability; Particle Size; Drug Stability; Taxoids; Antineoplastic Agents; Drug Liberation; Drug Carriers; Rats, Sprague-Dawley; Male; Drug Compounding; Rats
PubMed: 38846644
DOI: 10.2147/IJN.S457482 -
ESMO Open Jun 2024This phase II nonrandomized study evaluated the efficacy and safety of AZD4635 in combination with durvalumab (Arm A) or durvalumab plus cabazitaxel (Arm B) in patients...
BACKGROUND
This phase II nonrandomized study evaluated the efficacy and safety of AZD4635 in combination with durvalumab (Arm A) or durvalumab plus cabazitaxel (Arm B) in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel and ≥1 novel hormonal agent.
PATIENTS AND METHODS
The primary endpoint was radiographic progression-free survival (rPFS) per RECIST v1.1 (soft tissue) or the Prostate Cancer Clinical Trials Working Group 3 (bone). Secondary endpoints included safety, tolerability, overall survival, confirmed prostate-specific antigen (PSA) response, pharmacokinetics, and objective response rate. Enrollment in Arm A was stopped following a sponsor decision unrelated to safety. The study was stopped based on the planned futility analysis due to low PSA response in Arm B.
RESULTS
In the final analysis (1 November 2021), 30 patients were treated (Arm A, n = 2; Arm B, n = 28). The median rPFS in Arm B was 5.8 months (95% confidence interval 4.2-not calculable). Median rPFS was 5.8 months versus 4.2 months for patients with high versus low blood-based adenosine signature. The most common treatment-related adverse events in Arm B were nausea (50.0%), diarrhea (46.4%), anemia and neutropenia (both 35.7%), asthenia (32.1%), and vomiting (28.6%). Overall, AZD4635 in combination with durvalumab or AZD4635 in combination with cabazitaxel and durvalumab showed limited efficacy in patients with mCRPC.
CONCLUSIONS
Although the safety profile of both combinations was consistent with known safety data of the individual agents, the results of this trial do not support further development of the combinations.
Topics: Humans; Male; Prostatic Neoplasms, Castration-Resistant; Aged; Middle Aged; Antineoplastic Combined Chemotherapy Protocols; Antibodies, Monoclonal; Taxoids; Aged, 80 and over; Progression-Free Survival; Neoplasm Metastasis
PubMed: 38838502
DOI: 10.1016/j.esmoop.2024.103446 -
The Journal of International Medical... Jun 2024Pulmonary blastoma (PB) is a rare, highly malignant tumor prone to distant metastasis and recurrence, and the prognosis of these patients is often poor. We report a case... (Review)
Review
Pulmonary blastoma (PB) is a rare, highly malignant tumor prone to distant metastasis and recurrence, and the prognosis of these patients is often poor. We report a case of metastatic PB with a good prognosis with the aim of providing data to support a clinical diagnosis and treatment. In December 2015, a 43-year-old male patient was admitted to our hospital because of a cough and blood-stained sputum. Positron emission-computed tomography showed massive high-density imaging in the lower lobe of the right lung, with a maximum cross-section of 76 × 58 mm. Thoracoscopic-assisted right lower lobectomy with lymph node dissection was performed. After 1 month, computed tomography showed a high possibility of metastasis. The patient then received docetaxel and cisplatin chemotherapy for a total of six courses. After chemotherapy, enhanced computed tomography showed considerable absorption of pleural effusion, and a left lobe pulmonary nodule was not detected. The postoperative pathological diagnosis was PB, and epithelial and mesenchymal differentiation components were observed. The patient continued to visit the hospital regularly for re-examination and imaging examinations. Currently, no signs of recurrence or distant metastasis have been detected.
Topics: Humans; Male; Adult; Pulmonary Blastoma; Lung Neoplasms; Prognosis; Tomography, X-Ray Computed; Positron Emission Tomography Computed Tomography; Cisplatin; Pneumonectomy; Docetaxel
PubMed: 38835107
DOI: 10.1177/03000605241254778 -
Discover Oncology Jun 2024Dysregulation of zinc homeostasis is widely recognized as a hallmark feature of prostate cancer (PCa) based on the compelling clinical and experimental evidence....
BACKGROUND
Dysregulation of zinc homeostasis is widely recognized as a hallmark feature of prostate cancer (PCa) based on the compelling clinical and experimental evidence. Nevertheless, the implications of zinc dyshomeostasis in PCa remains largely unexplored.
METHODS
In this research, the zinc homeostasis pattern subtype (ZHPS) was constructed according to the profile of zinc homeostasis genes. The identified subtypes were assessed for their immune functions, mutational landscapes, biological peculiarities and drug susceptibility. Subsequently, we developed the optimal signature, known as the zinc homeostasis-related risk score (ZHRRS), using the approach won out in multifariously machine learning algorithms. Eventually, clinical specimens, Bayesian network inference and single-cell sequencing were used to excavate the underlying mechanisms of MT1A in PCa.
RESULTS
The zinc dyshomeostasis subgroup, ZHPS2, possessed a markedly worse prognosis than ZHPS1. Moreover, ZHPS2 demonstrated a more conspicuous genomic instability and better therapeutic responses to docetaxel and olaparib than ZHPS1. Compared with traditional clinicopathological characteristics and 35 published signatures, ZHRRS displayed a significantly improved accuracy in prognosis prediction. The diagnostic value of MT1A in PCa was substantiated through analysis of clinical samples. Additionally, we inferred and established the regulatory network of MT1A to elucidate its biological mechanisms.
CONCLUSIONS
The ZHPS classifier and ZHRRS model hold great potential as clinical applications for improving outcomes of PCa patients.
PubMed: 38833013
DOI: 10.1007/s12672-024-01006-z -
Yakugaku Zasshi : Journal of the... 2024Docetaxel (DTX) is a key drug used in perioperative chemotherapy for breast cancer. Edema is a known adverse effect of DTX, but its effect on health-related QOL (HRQOL)... (Observational Study)
Observational Study
Docetaxel (DTX) is a key drug used in perioperative chemotherapy for breast cancer. Edema is a known adverse effect of DTX, but its effect on health-related QOL (HRQOL) is unclear. In this study, we evaluated the effects of edema caused by administration of DTX on HRQOL in patients with early-stage breast cancer. We prospectively investigated patients diagnosed with early-stage breast cancer (stage I-III) who received 4 cycles of DTX as preoperative or postoperative chemotherapy between September 2021 and December 2022 at Yamanashi Prefectural Central Hospital. The circumference of each extremity was measured at each administration of DTX, and limb edema was evaluated by Common Terminology Criteria for Adverse Events version 5.0. HRQOL was evaluated using SF-12 version 2, which has a range of 0-100 (national standard, 50), and compared between the presence and absence of grade 2 or higher edema and between before and after administration of DTX. Twenty patients met the eligibility criteria and were included in the study. There was no difference in the HRQOL score according to whether grade 2 limb edema was present. The median HRQOL summary scores before and after administration of DTX were 51.1 and 50.8 (p=0.763), respectively, for mental health, 52.6 and 49.4 (p=0.005) for physical health, and 38.9 and 37.5 (p=1.000) for role/social health. We found no direct effect of DTX-induced limb edema on HRQOL in patients with early-stage breast cancer. However, HRQOL summary scores indicated that administration of DTX reduced physical health in these patients.
Topics: Humans; Docetaxel; Breast Neoplasms; Quality of Life; Female; Prospective Studies; Middle Aged; Edema; Aged; Neoplasm Staging; Adult; Extremities; Antineoplastic Agents; Perioperative Care
PubMed: 38825477
DOI: 10.1248/yakushi.23-00206 -
The Oncologist Jun 2024No consensus has been reached regarding the optimal chemotherapy for metastatic extramammary Paget's disease (EMPD), a rare cutaneous adenocarcinoma, because of the lack...
BACKGROUND
No consensus has been reached regarding the optimal chemotherapy for metastatic extramammary Paget's disease (EMPD), a rare cutaneous adenocarcinoma, because of the lack of solid evidence from prospective trials. However, the immunohistochemical profile of EMPD reportedly resembles that of breast cancer, particularly in terms of human epidermal growth factor receptor 2 (HER2) expression, suggesting that HER2 is a promising therapeutic target for advanced HER2-positive EMPD.
METHODS
In this phase II single-arm trial, 13 Japanese patients received intravenous trastuzumab (loading dose of 8 mg/kg and maintenance dose of 6 mg/kg) and docetaxel (75 mg/m2) every 3 weeks for up to 2 years. The docetaxel dose was reduced or discontinued according to its toxicity. The primary trial endpoints were objective response rate (ORR) after 3 cycles of treatment and safety throughout the study period.
RESULTS
All 13 patients completed 3 cycles of combination therapy. The median follow-up was 27.9 months. The ORR was 76.9% (n = 10/13; 90% CI, 50.5-93.4). Frequently observed adverse events were neutropenia (100%), hypoalbuminemia (84.6%), and mucocutaneous infection (84.6%), all of which were well tolerated.
CONCLUSION
The combination of docetaxel and trastuzumab demonstrated a favorable clinical effect and acceptable tolerability, which makes it a good treatment option for HER2-positive metastatic EMPD (ClinicalTrials.gov Identifier: UMIN000021311, jRCTs031180073).
PubMed: 38823035
DOI: 10.1093/oncolo/oyae097