Potential utility of pretreatment serum miRNAs for optimal treatment selection in advanced high-grade serous ovarian cancer.

OBJECTIVE: The primary treatment of patients with advanced ovarian cancer is selected from whether primary debulking surgery or neoadjuvant chemotherapy. We investigated whether pretreatment serum microRNA profiles are useful for selecting patients with advanced high-grade serous ovarian cancer who obtain better outcomes from undergoing primary debulking surgery or neoadjuvant chemotherapy. METHODS: Consecutive patients with clinical stage IIIB-IVB and serum microRNA data were selected. Patients who underwent primary debulking surgery or neoadjuvant chemotherapy were subjected to 1:1 propensity score matching before comparing their progression-free survival using Cox modelling. Progression-free probabilities for the selected microRNA profiles were calculated, and the estimated progression-free survival with the recommended primary treatment was determined and compared with the actual progression-free survival of the patients. RESULTS: Of the 108 patients with stage IIIB-IVB disease, the data of 24 who underwent primary debulking surgery or neoadjuvant chemotherapy were compared. Eleven and three microRNAs were independent predictors of progression-free survival in patients who underwent primary debulking surgery and neoadjuvant chemotherapy, respectively. Two microRNAs correlated significantly with complete resection of the tumours in primary debulking surgery. No differences were found between the actual and estimated progression-free survival in the primary debulking surgery and neoadjuvant chemotherapy groups (P > 0.05). The recommended and actual primary treatments were identical in 27 (56.3%) of the 48 patients. The median improved survival times between recommended and actual treatment were 11.7 and 32.6 months for patients with actual primary debulking surgery and neoadjuvant chemotherapy, respectively. CONCLUSIONS: Pretreatment microRNA profiles could be used to select subgroups of patients who benefited more from primary debulking surgery or neoadjuvant chemotherapy and might contribute to selecting the optimal primary treatment modality in advanced high-grade serous ovarian cancer patients.

Suggestive answers strategy in human-chatbot interaction: a route to engaged critical decision making.

In this study, we proposed a novel chatbot interaction strategy based on the suggestive ending of answers. This strategy is inspired by the cliffhanger ending narrative technique, which ends a story without specifying conclusions to spark readers' curiosity as to what will happen next and is often used in television series. Common chatbots provide relevant and comprehensive answers to users' questions. In contrast, chatbots with our proposed strategy end their answers with hints potentially interest-triggering users. The suggestive ending strategy aims to stimulate users' inquisition for critical decision-making, relating to a psychological phenomenon where humans are often urged to finish the uncompleted tasks they have initiated. We demonstrated the implication of our strategy by conducting an online user study involving 300 participants, where they used chatbots to perform three decision-making tasks. We adopted a between-subjects factorial experimental design and compared between the following UIs: (1) plain chatbot-it provides a generated answer when participants issue a question; (2) expositive chatbot-it provides a generated answer for a question, adding short summaries of a positive and negative person's opinion for the answer; (3) suggestive chatbot-it provides a generated answer for a question, which ends with a suggestion of a positive and negative person for the answer. We found that users of the suggestive chatbot were inclined to ask more questions to the bot, engage in prolonged decision-making and information-seeking actions, and formulate their opinions from various perspectives. These findings vary with the users' experience with plain and expositive chatbots.

Lymphovascular invasion is associated with poor long-term outcomes in patients with pT1N0-3 or pT2-3N0 remnant gastric cancer: a retrospective cohort study.

BACKGROUND: Lymphovascular invasion (LVI) is a poor prognostic factor in various malignancies. However, its prognostic effect in remnant gastric cancer (RGC) remains unclear. We examined the correlation between LVI and disease prognosis in patients with T1N0-3 or T2-3N0 RGC in whom adjuvant chemotherapy was not indicated and a treatment strategy was not established. METHODS: We retrospectively analyzed patients with T1N0-3 and T2-3N0 RGC who underwent curative surgery at the Kyoto Prefectural University of Medicine between 1997 and 2019 and at the Kyoto Chubu Medical Center between 2009 and 2019. RESULTS: Fifteen of 38 patients (39.5%) with RGC were positive for LVI. Patients with LVI had a significantly poorer prognosis for both overall survival ([OS]: P = 0.006) and recurrence-free survival ([RFS]: P = 0.001) than those without LVI. Multivariate analyses using the Cox proportional hazards model revealed LVI as an independent prognostic factor affecting OS (P = 0.024; hazard ratio 8.27, 95% confidence interval:1.285-161.6) and RFS (P = 0.013; hazard ratio 8.98, 95% confidence interval:1.513-171.2). CONCLUSIONS: LVI is a prognostic factor for patients with T1N0-3 or T2-3N0 RGC. Evaluating LVI may be useful for determining treatment strategies for RGC.

Risk factors for liver dysfunction and their clinical importance after gastric cancer surgery.

Postoperative hepatobiliary enzyme abnormalities often present as postoperative liver dysfunction in patients with gastric cancer (GC). This study aimed to identify the risk factors for postoperative liver dysfunction and their clinical impact after GC surgery. We retrospectively analyzed the data of 124 patients with GC who underwent laparoscopic or robotic surgery at Kyoto Prefectural University of Medicine between 2017 and 2019. Twenty (16.1%) patients with GC developed postoperative liver dysfunction (Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 ≥ Grade 3). Univariate analyses identified robotic surgery as a risk factor for postoperative liver dysfunction (P = 0.005). There was no correlation between the postoperative liver dysfunction status and postoperative complications or postoperative hospital stays. Patients with postoperative liver dysfunction did not have significantly worse overall survival (P = 0.296) or recurrence-free survival (P = 0.565) than those without postoperative liver dysfunction. Robotic surgery is a risk factor for postoperative liver dysfunction; however, postoperative liver dysfunction does not affect short or long-term outcomes.

Impact of hypoglycemia after gastrectomy on Global Leader Initiative on Malnutrition-defined malnutrition: a retrospective study.

PURPOSE: The Global Leader Initiative on Malnutrition (GLIM) criteria were developed in 2018 as a global indicator of malnutrition, and the term 'malnutrition-sarcopenia syndrome' was established. Recently, it has been reported that fluctuations in blood glucose are related to sarcopenia. In this study, we investigated the effects of glucose fluctuations on malnutrition after gastrectomy using a continuous glucose monitoring (CGM) device. METHODS: We analyzed the data of 69 patients with gastric cancer (GC) who underwent curative gastrectomy between November 2017 and December 2020. CGM was performed over a 2-week period at 1 month and 1 year after surgery. The GLIM criteria included weight loss, the body mass index (BMI), and the psoas muscle mass index (PMI). RESULTS: One year after surgery, 25 and 35 patients had severe and moderate malnutrition, respectively. The time below range (TBR) (percent of time the glucose concentration was < 70 mg/dL) and nocturnal (00:00-06:00) TBR were significantly higher in the severe malnutrition group than in the other groups (TBR: normal/moderate 17.9% vs. severe 21.6%, P = 0.039, nocturnal TBR; normal/moderate 30.6% vs. severe 41.1%, P = 0.034). CONCLUSIONS: Post-gastrectomy hypoglycemia, including long nocturnal hypoglycemia, was higher in severely malnourished patients than in other patients even 1 year after surgery. Prevention of nocturnal hypoglycemia may be the key to improving malnutrition following gastrectomy.

Assessing ulnar neuropathy at the elbow using magnetoneurography.

OBJECTIVE: To measure neuromagnetic fields of ulnar neuropathy patients at the elbow after electrical stimulation and evaluate ulnar nerve function at the elbow with high spatial resolution. METHODS: A superconducting quantum interference device magnetometer system recorded neuromagnetic fields of the ulnar nerve at the elbow after electrical stimulation at the wrist in 16 limbs of 16 healthy volunteers and 21 limbs of 20 patients with ulnar neuropathy at the elbow. After artifact removal, neuromagnetic field signals were processed into current distributions, which were superimposed onto X-ray images for visualization. RESULTS: Based on the results in healthy volunteers, conduction velocity of 30 m/s or 50% attenuation in current amplitude was set as the reference value for conduction disturbance. Of the 21 patient limbs, 15 were measurable and lesion sites were detected, whereas 6 limbs were unmeasurable due to weak neuromagnetic field signals. Seven limbs were deemed normal by nerve conduction study, but 5 showed conduction disturbances on magnetoneurography. CONCLUSIONS: Measuring the magnetic field after nerve stimulation enabled visualization of neurophysiological activity in patients with ulnar neuropathy at the elbow and evaluation of conduction disturbances. SIGNIFICANCE: Magnetoneurography may be useful for assessing lesion sites in patients with ulnar neuropathy at the elbow.

Analysis of the responsiveness to antiandrogens in multiple breast cancer cell lines.

Antiandrogens were originally developed as therapeutic agents for prostate cancer but are also expected to be effective for breast cancer. However, the role of androgen signaling in breast cancer has long been controversial due to the limited number of experimental models. Our study aimed to comprehensively investigate the efficacy of antiandrogens on breast cancer. In the present study, a total of 18 breast cancer cell lines were treated with the agonist or antagonists of the androgen receptor (AR). Among the 18 cell lines tested, only T-47D cells proliferated in an androgen-dependent manner, while the other cell lines were almost irresponsive to AR stimulation. On the other hand, treatment with AR antagonists at relatively high doses suppressed the proliferation of not only T-47D cells but also some other cell lines including AR-low/negative cells. In addition, expression of the full-length AR and constitutively active AR splice variants, AR-V7 and ARV567es, was not correlated with sensitivity to AR antagonists. These data suggest that the antiproliferative effect of AR antagonists is AR-independent in some cases. Consistently, proliferation of AR-knockout BT-549 cells was inhibited by AR antagonists. Identification of biomarkers would be necessary to determine which breast cancer patients will benefit from these drugs.

Uterine leiomyosarcoma cell-derived extracellular vesicles induce the formation of cancer-associated fibroblasts.

OBJECTIVE: Uterine leiomyosarcoma (ULMS) is a rare malignant tumor, which is aggressive, and has a poor prognosis even during its early stages. Extracellular vesicles (EVs) carry cargo, such as microRNAs (miRNAs), which are involved in intercellular communication in the tumor microenvironment and other processes. Because there are no studies on EV-related miRNAs in ULMS, we identified EV-related miRNAs in ULMS and examined their function. METHODS: Small EVs (sEVs) and medium/large EVs (m/lEVs) were extracted from ULMS cells by ultracentrifugation and their basic characteristics were evaluated. Then, small RNA sequencing was done to obtain EV-related miRNA profiles. Next, miRNA expression levels in sera and tissues of ULMS patients were compared with those of myoma patients. RESULTS: miR-654-3p and miR-369-3p were indicated to be highly expressed in both sera and tissues of ULMS patients. These two miRNAs are also highly expressed in ULMS cell lines and ULMS-derived EVs. Some cancer-associated fibroblast (CAF) markers were increased when fibroblasts were treated with ULMS-derived EVs. Furthermore, fibroblasts took up EVs derived from ULMS as determined by confocal laser microscopy. In addition, the transfection of the two candidate miRNAs into fibroblasts significantly increased some CAF markers, particularly ACTA2. CONCLUSION: miR-654-3p and miR-369-3p are highly expressed in ULMS-derived EVs, indicating that these EV-related miRNAs induce the formation of cancer-associated fibroblasts.

Drug-induced lung injury in a patient treated with prior atezolizumab and subsequent sotorasib: A case report.

We report a case of drug-induced lung injury treated with prior atezolizumab and subsequent sotorasib. The patient was a 62-year-old woman with lung adenocarcinoma harbouring a KRAS G12C mutation that was resistant to chemotherapy, including immune checkpoint inhibitors. Cough and dyspnea appeared on day 80 after sotorasib was administered as second-line therapy, and chest computed tomography revealed ground glass opacities in all lung lobes. Bronchoalveolar lavage fluid showed an increased total cell count with lymphocyte predominance. The patient was considered to have lung injury caused by prior atezolizumab or sotorasib administration. Withdrawal of sotorasib did not improve symptoms and shadows in both lungs. We administered moderate-dose prednisolone and the lung disorder quickly resolved. Prednisolone tapering was completed in 2 months, followed by several months without relapse. Definitive identification of the responsible drug for the drug-induced lung injury proved challenging in the setting of exposure to multiple potential inciting agents. There is a need for high levels of clinical suspicion for timely evaluation and management.

A case of massive hemoptysis caused by lung cancer saved by V-V ECMO and hemostasis achieved by radiotherapy.

Massive hemoptysis is one of the fatal complications of lung cancer. There is no established standard treatment method for it, and it often causes sudden suffocation, and some cases may be difficult to save. A 63-year-old man was admitted to the hospital with dyspnea, and developed massive hemoptysis from lung cancer shortly after admission. The tumor had obstructed the right main bronchus and had invaded the right pulmonary artery. Surgery and interventional radiology were judged impossible. The patient was successfully saved by the introduction of Veno-Venous Extra Corporeal Membrane Oxygenation (V-V ECMO), and hemostasis was obtained by radiotherapy. Two months after completion of radiotherapy, he was weaned off the ventilator and discharged on his own. He died of increased peritoneal dissemination and other complications 1 year and 1 month later, but no recurrence of hemoptysis was noted until his death. We experienced a case of massive hemoptysis in which V-V ECMO and radiation therapy succeeded in saving life and stopping bleeding. The use of V-V ECMO by emergency care teams and multimodality therapy, including radiotherapy, were effective for massive hemoptysis from lung cancer.

Collagen induction of immune cells in the mammary glands during pregnancy.

The mammary glands are dynamic tissues affected by pregnancy-related hormones during the pregnancy-lactation cycle. Collagen production and its dynamics are essential to the remodeling of the mammary glands. Alterations of the mammary microenvironment and stromal cells during the pregnancy-lactation cycle are important for understanding the physiology of the mammary glands and the development of breast tumors. In this study, we performed an evaluation of collagen dynamics in the mammary fat pad during the pregnancy-lactation cycle. Reanalysis of single-cell RNA-sequencing (scRNA-Seq) data showed the ectopic collagen expression in the immune cells and cell-cell interactions for collagens with single-cell resolution. The scRNA-Seq data showed that type I and type III collagen were produced not only by stromal fibroblasts but also by lymphoid and myeloid cell types in the pregnancy phase. Furthermore, the total cell-cell interaction score for collagen interactions was dramatically increased in the pregnancy tissue. The data presented in this study provide evidence that immune cells contribute, at least in part, to mammary collagen dynamics. Our findings suggest that immune cells, including lymphoid and myeloid cells, might be supportive members of the extracellular matrix orchestration in the pregnancy-lactation cycle of the mammary glands.NEW & NOTEWORTHY Our study evaluated mammary gland collagen dynamics during the pregnancy-lactation cycle using single-cell RNA-sequencing data. We found ectopic collagen expression in immune cells and an increase in collagen interactions during pregnancy. Type I and type III collagen were produced by lymphoid, myeloid, and stromal fibroblast cells during pregnancy. These findings suggest that immune cells, including lymphoid and myeloid cells, play a crucial role in supporting the extracellular matrix in mammary glands during pregnancy-lactation cycles.

Metastatic potentials classified with hypoxia-inducible factor 1 downstream genes in pan-cancer cell lines.

Hypoxia-inducible factor 1 (HIF1) is a transcription factor that is stabilized under hypoxia conditions via post-translational modifications. HIF1 regulates tumor malignancy and metastasis by gene transcriptions, such as Warburg effect and angiogenesis-related genes, in cancer cells. However, the HIF1 downstream genes show varied expressional patterns in different cancer types. Herein, we performed the hierarchical clustering based on the HIF1 downstream gene expression patterns using 1406 cancer cell lines crossing 30 types of cancer to understand the relationship between HIF1 downstream genes and the metastatic potential of cancer cell lines. Two types of cancers, including bone and breast cancers, were classified based on HIF1 downstream genes with significantly altered metastatic potentials. Furthermore, different HIF1 downstream gene subsets were extracted to discriminate each subtype for these cancer types. HIF1 downstream subtyping classification will help to understand the novel insight into tumor malignancy and metastasis in each cancer type.

Prognostic impact of the distance from the root of splenic artery to tumor in the patients with pancreatic body or tail cancer.

BACKGROUND: The impact of the distance from the root of splenic artery to tumor (DST) on the prognosis and optimal surgical procedures in the patients with pancreatic body/tail cancer has been unclear. METHODS: We retrospectively analyzed 94 patients who underwent distal pancreatectomy (DP) and 17 patients who underwent DP with celiac axis resection (DP-CAR) between 2008 and 2018. RESULTS: The 111 patients were assigned by DST length (in mm) as DST = 0: n = 14, 0

Cancer Stem Cells of Hepatocellular Carcinoma Are Suppressed by the Voltage-gated Calcium Channel Inhibitor Amlodipine.

BACKGROUND/AIM: The membrane transporters activated in cancer stem cells (CSCs) are the target of novel cancer therapies for hepatocellular carcinoma (HCC). The present investigation demonstrated the expression profiles of ion channels in CSCs of HCC. MATERIALS AND METHODS: Cells that highly expressed aldehyde dehydrogenase 1 family member A1 (ALDH1A1) were separated from HepG2 cells, a human HCC cell line, by fluorescence-activated cell sorting, and CSCs were identified based on the formation of tumorspheres. Gene expression profiles in CSCs were investigated using microarray analysis. RESULTS: Among HepG2 cells, ALDH1A1 messenger RNA level was higher in CSCs than in non-CSCs. Furthermore, CSCs exhibited resistance to cisplatin and had the capacity to redifferentiate. The results of the microarray analysis of CSCs showed the up-regulated expression of several genes related to ion channels, such as calcium voltage-gated channel auxiliary subunit gamma 4 (CACNG4). The cytotoxicity of the CACNG4 inhibitor amlodipine was higher at lower concentrations in CSCs than in non-CSCs, and markedly decreased the number of tumorspheres. The cell population among HepG2 cells that highly expressed ALDH1A1 was also significantly reduced by this inhibitor. CONCLUSION: CACNG4 plays a role in maintaining CSCs, and its inhibitor, amlodipine, could potentially be a targeted therapeutic agent against HCC.

Cancer-prone Phenotypes and Gene Expression Heterogeneity at Single-cell Resolution in Cigarette-smoking Lungs.

Single-cell RNA sequencing (scRNA-seq) technologies have been broadly utilized to reveal molecular mechanisms of respiratory pathology and physiology at single-cell resolution. Here, we established single-cell meta-analysis (scMeta-analysis) by integrating data from eight public datasets, including 104 lung scRNA-seq samples with clinicopathologic information and designated a cigarette-smoking lung atlas. The atlas revealed early carcinogenesis events and defined the alterations of single-cell transcriptomics, cell population, and fundamental properties of biological pathways induced by smoking. In addition, we developed two novel scMeta-analysis methods: VARIED (Visualized Algorithms of Relationships In Expressional Diversity) and AGED (Aging-related Gene Expressional Differences). VARIED analysis revealed expressional diversity associated with smoking carcinogenesis. AGED analysis revealed differences in gene expression related to both aging and smoking status. The scMeta-analysis paves the way to utilize publicly-available scRNA-seq data and provide new insights into the effects of smoking and into cellular diversity in human lungs, at single-cell resolution. SIGNIFICANCE: The atlas revealed early carcinogenesis events and defined the alterations of single-cell transcriptomics, cell population, and fundamental properties of biological pathways induced by smoking.

Utility of desflurane as an anesthetic in motor-evoked potentials in spine surgery and the facilitating effect in tetanic stimulation of bilateral median nerves.

Although desflurane is a safe and controllable inhalation anesthetic used in spinal surgery, to our knowledge, there have been no reports of successful motor-evoked potential (MEP) recordings under general anesthesia with desflurane alone. A high desflurane concentration may reduce the risk of intraoperative awareness but can also reduce the success of MEP recording. Therefore, we aimed to evaluate the reliability of MEP monitoring and investigate whether tetanic stimulation can augment MEP amplitude under general anesthesia with high-concentration desflurane during spinal surgery. We prospectively evaluated 46 patients who were scheduled to undergo lumbar surgery at a single center between 2018 and 2020. Anesthesia was maintained with an end-tidal concentration of 4% desflurane and remifentanil. Compound muscle action potentials were recorded bilaterally from the abductor pollicis brevis, abductor hallucis, tibialis anterior, gastrocnemius, and quadriceps. For post-tetanic MEPs (p-MEPs), tetanic stimulation was applied to the median nerves (p-MEPm) and tibial nerves (p-MEPt) separately before transcranial stimulation. The average success rates for conventional MEP (c-MEP), p-MEPm, and p-MEPt were 77.9%, 80%, and 79.3%, respectively. The p-MEPm amplitudes were significantly higher than the c-MEP amplitudes in all muscles (P < 0.05), whereas the p-MEPt amplitudes were not significantly different from the c-MEP amplitudes. The MEP recording success rates for the gastrocnemius and quadriceps were inadequate. However, bilateral median nerve tetanic stimulation can effectively augment MEPs safely under general anesthesia with high-concentration desflurane in patients who undergo spinal surgery.

Spatial exosome analysis using cellulose nanofiber sheets reveals the location heterogeneity of extracellular vesicles.

Extracellular vesicles (EVs), including exosomes, are recognized as promising functional targets involved in disease mechanisms. However, the intravital heterogeneity of EVs remains unclear, and the general limitation for analyzing EVs is the need for a certain volume of biofluids. Here, we present cellulose nanofiber (CNF) sheets to resolve these issues. We show that CNF sheets capture and preserve EVs from ~10 µL of biofluid and enable the analysis of bioactive molecules inside EVs. By attaching CNF sheets to moistened organs, we collect EVs in trace amounts of ascites, which is sufficient to perform small RNA sequence analyses. In an ovarian cancer mouse model, we demonstrate that CNF sheets enable the detection of cancer-associated miRNAs from the very early phase when mice did not have apparent ascites, and that EVs from different locations have unique miRNA profiles. By performing CNF sheet analyses in patients, we identify further location-based differences in EV miRNA profiles, with profiles reflecting disease conditions. We conduct spatial exosome analyses using CNF sheets to reveal that ascites EVs from cancer patients exhibit location-dependent heterogeneity. This technique could provide insights into EV biology and suggests a clinical strategy contributing to cancer diagnosis, staging evaluation, and therapy planning.

Small Extracellular Vesicles from adipose-derived stem cells suppress cell proliferation by delivering the let-7 family of microRNAs in ovarian cancer.

INTRODUCTION: Ovarian cancer is the leading cause of death among women with gynecological cancer, and novel treatment options are urgently needed. Extracellular vesicles (EVs), including exosomes, may be one of the most promising therapeutic tools for various diseases. In this study, we aimed to investigate the therapeutic effects of adipose-derived stem cell-derived EVs (ADSC-EVs) on ovarian cancer cell lines. MATERIALS AND METHODS: ADSCs and the ovarian cancer cell lines SKOV3 and OV90 were used for analysis. ADSC-EVs were isolated through ultracentrifugation and validated using a cryotransmission electron microscope, nanoparticle tracking analysis, and western blotting. Then, the effect of ADSC-EVs on ovarian cancer cells was investigated using IncuCyte and microRNA sequencing. Moreover, the potential functions of miRNAs were evaluated by gain-of function analysis and in silico analysis. RESULTS: ADSC-EVs suppressed SKOV3 and OV90 cell proliferation. In particular, small EVs (sEVs) from ADSCs exhibited a stronger antitumor effect than ADSC-medium/large EVs (m/lEVs). Comparison of the miRNA profiles between ADSC-sEVs and ADSC-m/lEVs, along with downstream pathway analysis, suggested the involvement of the let-7 family. Overexpression of hsa-let-7b-5p and hsa-let-7e-5p significantly suppressed the proliferation of SKOV3 cells. In silico analysis revealed that four potential target genes of hsa-let-7b-5p and hsa-let-7e-5p were significantly associated with the prognoses of the patients. CONCLUSION: ADSC-sEVs had a stronger antitumor effect than ADSC-m/lEVs. Hsa-let-7b-5p and hsa-let-7e-5p, which are highly abundant in ADSC-sEVs, suppressed cell proliferation. These findings may open up new possibilities for therapeutic approaches using ADSC-sEVs.

[Extracellular vesicle-mediated drug resistance in multiple myeloma].

Because of innovative therapeutic agents such as proteasome inhibitors, immunomodulatory medicines, and antibody medications, the prognosis of multiple myeloma (MM) has considerably improved in recent years. However, the prognosis for MM patients with treatment resistance and extramedullary illness remains poor. The interaction between MM cells and their surrounding cells in the bone marrow microenvironment is critical for medication resistance development. Many issues cannot be explained by liquid factors, such as cytokines and chemokines. Extracellular vesicles (EVs) have gained interest due to their role in the advancement of several forms of cancers. In this article, we primarily summarize MM drug resistance and examine the most recent articles on small-EVs (particularly exosomes) that contribute to MM drug resistance acquisition.