MYC Inhibition Potentiates CD8+ T Cells Against Multiple Myeloma and Overcomes Immunomodulatory Drug Resistance.

PURPOSE: Immunomodulatory drugs (IMiDs), such as lenalidomide and pomalidomide, are a cornerstone of multiple myeloma (MM) therapies, yet the disease inevitably becomes refractory. IMiDs exert cytotoxicity by inducing cereblon-dependent proteasomal degradation of IKZF1 and IKZF3, resulting in downregulation of the oncogenic transcription factors IRF4 and MYC. To date, clinical IMiD resistance independent of cereblon or IKZF1/3 has not been well explored. Here, we investigated the roles of IRF4 and MYC in this context. EXPERIMENTAL DESIGN: Using bone marrow aspirates from patients with IMiD-naïve or refractory MM, we examined IKZF1/3 protein levels and IRF4/MYC gene expression following ex vivo pomalidomide treatment via flow cytometry and qPCR. We also assessed exvivo sensitivity to the MYC inhibitor MYCi975 using flow cytometry. RESULTS: We discovered that although pomalidomide frequently led to IKZF1/3 degradation in MM cells, it did not affect MYC gene expression in most IMiD-refractory samples. We subsequently demonstrated that MYCi975 exerted strong anti-MM effects in both IMiD-naïve and -refractory samples. Unexpectedly, we identified a cluster of differentiation 8+ (CD8+ T) cells from patients with MM as crucial effectors of MYCi975-induced cytotoxicity in primary MM samples, and we discovered that MYCi975 enhanced the cytotoxic functions of memory CD8+ T cells. We lastly observed synergy between MYCi975 and pomalidomide in IMiD-refractory samples, suggesting that restoring MYC downregulation can re-sensitize refractory MM to IMiDs. CONCLUSIONS: Our study supports the concept that MYC represents an Achilles' heel in MM across disease states and that MYCi975 may be a promising therapeutic for patients with MM, particularly in combination with IMiDs.

CD46-ADC Reduces the Engraftment of Multiple Myeloma Patient-Derived Xenografts.

An antibody-drug conjugate (ADC) targeting CD46 conjugated to monomethyl auristatin has a potent anti-myeloma effect in cell lines in vitro and in vivo, and patient samples treated ex vivo. Here, we tested if CD46-ADC may have the potential to target MM-initiating cells (MM-ICs). CD46 expression was measured on primary MM cells with a stem-like phenotype. A patient-derived xenograft (PDX) model was implemented utilizing implanted fetal bone fragments to provide a humanized microenvironment. Engraftment was monitored via serum human light chain ELISA, and at sacrifice via bone marrow and bone fragment flow cytometry. We then tested MM regeneration in PDX by treating mice with CD46-ADC or the nonbinding control-ADC. MM progenitor cells from patients that exhibit high aldehyde dehydrogenase activity also have a high expression of CD46. In PDX, newly diagnosed MM patient samples engrafted significantly more compared to relapsed/refractory samples. In mice transplanted with newly diagnosed samples, CD46-ADC treatment showed significantly decreased engraftment compared to control-ADC treatment. Our data further support the targeting of CD46 in MM. To our knowledge, this is the first study to show preclinical drug efficacy in a PDX model of MM. This is an important area for future study, as patient samples but not cell lines accurately represent intratumoral heterogeneity.

The effects of male anxiety and depression on IVF outcomes.

STUDY QUESTION: What are the effects of male anxiety and depression on IVF outcomes? SUMMARY ANSWER: Men with anxiety had lower final total motile sperm counts (fTMSC) during IVF compared to men without anxiety; however, there were no differences in live birth rates (LBRs). WHAT IS KNOWN ALREADY: Studies have shown that male anxiety causes low sperm motility, worse sperm morphology, and increased DNA fragmentation, which are known to be influential factors on fertilization rates and embryo quality during IVF. However, data are lacking on whether there is a direct association between male anxiety and/or depression and IVF outcomes. STUDY DESIGN, SIZE, DURATION: This was a survey-based, retrospective cohort study completed at a single, large hospital-affiliated fertility center with 222 respondents who underwent IVF with or without ICSI. The study was conducted between 6 September 2018 and 27 December 2022. PARTICIPANTS/MATERIALS, SETTING, METHODS: Male partners of couples who underwent IVF or IVF/ICSI completed a Hospital Anxiety and Depression Scale (HADS) questionnaire. They were separated into two groups for both anxiety (HADS-A ≥ 8 or HADS-A < 8) and depression (HADS-D ≥ 8 or HADS-D < 8). Men with an elevated HADS-A or HADS-D score ≥8 were considered to have anxiety or depression, respectively. The primary outcome was LBR. Secondary outcomes included semen parameters at the time of IVF, cycle outcomes, pregnancy outcomes, and prevalence of erectile dysfunction and low libido. MAIN RESULTS AND THE ROLE OF CHANCE: There were a total of 222 respondents, of whom 22.5% had a HADS-A ≥ 8 and 6.5% had a HADS-D ≥ 8. The average age of respondents was 37.38 ± 4.90 years old. Antidepressant use was higher in the respondents with a HADS-A or HADS-D ≥ 8 (P < 0.05). Smoking use was similar between groups for both HADS-A and HADS-D (P > 0.05). When adjusted for male BMI, antidepressant use and smoking, men with a HADS-A or HADS-D ≥ 8 had similar rates of erectile dysfunction (adjusted relative risk (aRR) = 1.12 (95% CI 0.60, 2.06)) and low libido (aRR = 1.70 (95% CI 0.91, 3.15)) compared to those with a HADS-A or HADS-D ≤ 8. Men with a HADS-A ≥ 8 were more likely to have a lower fTMSC on the day of oocyte retrieval (11.8 ≥ 8 vs 20.1 < 8, adjusted ß = -0.66 (95% CI -1.22, -0.10)). However, the LBR per embryo transfer (ET) was similar between the HADS-A groups (43.2% ≥8 vs 45.1% <8, adjusted relative risk = 0.90 (95% CI 0.65, 1.06)). Although depression was uncommon in the entire cohort, the HADS-D groups were clinically similar for fTMSC (18.7 ≥ 8 vs 16.0 < 8) and LBR per ET (46.7% ≥8 vs 45.4% <8). LIMITATIONS, REASONS FOR CAUTION: Limitations of our study are the survey-based design, the lack of sperm morphology assessment at the time of IVF, our inability to fully assess the HADS-D ≥ 8 cohort due to the small sample size and the large Caucasian demographic. WIDER IMPLICATIONS OF THE FINDINGS: Couples undergoing IVF have an increased likelihood of suffering from anxiety and/or depression. There is currently a debate on whether or not men should be treated with antidepressants while attempting to conceive due to potential detrimental effects on sperm quality. Our study shows that, regardless of antidepressant use, couples with men who did or did not report anxiety and/or depression have similar LBRs when undergoing IVF. Therefore, it is important to assess both partners for mental health and to not withhold treatment due to a concern about a potential impact of antidepressants or anxiety/depression on sperm quality. STUDY FUNDING/COMPETING INTEREST(S): There was no funding to report for this study. Z.W. is a contributing author for UptoDate. S.S.S. is on the advisory board for Ferring Pharmaceuticals. E.G. was a medical consultant for Hall-Matson Esq, Teladoc, and CRICO and is a contributing author for UptoDate. The remaining authors have nothing to report. TRIAL REGISTRATION NUMBER: N/A.

CD38 antibody re-treatment in daratumumab-refractory multiple myeloma after time on other therapies.

Monoclonal antibodies targeting CD38 are important for treatment of both newly diagnosed and relapsed multiple myeloma (MM). Daratumumab and isatuximab are anti-CD38 antibodies with the US Food and Drugs Administration approval in multiple different combinations. Despite good initial efficacy, patients inevitably develop drug resistance. Whether patients can be effectively re-treated with these antibodies in subsequent lines of therapy is unclear. Thus far, studies have mostly been limited to clinical retrospectives with short washout periods. To answer whether patients regain sensitivity after longer washouts, we used ex vivo sensitivity testing to isolate the anti-CD38 antibody-specific cytotoxicity in samples obtained from patients who had been exposed to and then off daratumumab for up to 53 months. MM cells from patients who had been off daratumumab for >1 year showed greater sensitivity than those with <1 year, although they still were less sensitive than those who were daratumumab naïve. CD38 expression on MM cells gradually recovered, although, again, not to the level of anti-CD38 antibody-naïve patients. Interestingly, low MM CD38 explained only 45% of cases identified to have daratumumab resistance. With clinical follow-up, we found ex vivo sensitivity predicted subsequent clinical response but CD38 overexpression did not. Patients clinically re-treated with anti-CD38 antibodies had <6 months of clinical benefit, but 1 patient who was daratumumab exposed but not refractory achieved complete response lasting 13 months. We conclude that transient efficacy can be achieved by waiting 1 year before CD38 antibody rechallenge, but this approach may be best used as a bridge to, or after, chimeric antigen receptor T-cell therapy.

Near-infrared and hysteroscopy-guided robotic excision of uterine isthmocele with laser fiber: a novel high-precision technique.

OBJECTIVE: To describe a novel high-precision technique for robotic excision of uterine isthmocele, employing a carbon dioxide laser fiber, under hysteroscopic guidance, and near-infrared guidance. DESIGN: Video article. PATIENT(S): A 36-year-old multipara with 3 prior cesarean sections presented to our infertility clinic with secondary infertility. The patient had been trying to conceive for 6 months without success. The patient underwent a hystero-salpingo contrast sonography that identified a large cesarean scar defect with a 1.4-mm residual myometrial thickness (RMT). The patient was counseled on surgical management with robotic approach because of RMT <3 mm precluding her from hysteroscopic resection and the potential risk for a cesarean scar ectopic or abnormal placentation if she were to become pregnant in the future. She elected to undergo excision and repair and informed consent was obtained from the patient. INTERVENTION(S): The robot was docked for traditional gynecologic robotic surgery. The uterus was injected with 5 units of vasopressin. We used a carbon dioxide laser fiber (Lumenis FIberLase) at a power of 5 watts as the sole energy source for dissection. The bladder was dissected off the uterus to identify the general area of the isthmocele. At that point, diagnostic hysteroscopy was performed using a 30-degree 5-mm hysteroscope (Karl Storz) to identify and enter the isthmocele. Near-infrared vision (da Vinci Firefly, Intuitive USA) was activated to precisely outline the extent of the isthmocele, which was not visible with simple transillumination from the hysteroscope. We proceeded with laser excision in infrared/gray scale using the laser at a power of 20 watts removing the entire area that was highlighted by the Firefly. After full excision of the isthmocele, the hysteroscope was removed and was eventually replaced by a uterine manipulator (ConMed VCare DX). The hysterotomy was closed with a 2-layer closure: 4 mattress sutures of 2-0 Vicryl (Ethicon) followed by a running 2-0 PDS Stratafix (Ethicon). The peritoneal layer was closed over these 2 layers with 2-0 PDS Stratafix (Ethicon) in a running fashion. The uterine manipulator was removed and a 14 French Malecot catheter (Bard) was placed in the uterine cavity to allow the healing to proceed with minimal risk of cervical stenosis. The bladder was backfilled to ensure integrity of the bladder wall. Interceed adhesion barrier (Gynecare) was then placed over the area of the repair and the procedure was concluded. The patient included in this video gave consent for publication of the video and posting of the video online including social media, the journal website, scientific literature websites (such as PubMed, ScienceDirect, Scopus, etc.), and other applicable sites. MAIN OUTCOME MEASURE(S): Completion of excision and repair of cesarean scar defect without surgical complications. RESULT(S): Robotic excision and repair of a sizable uterine isthmocele with carbon dioxide laser fiber and da Vinci Firefly was completed successfully without any surgical complications. Diagnostic hysteroscopy was used to positively identify the isthmocele and provide transillumination. However, the thickness of the cervical myometrium only allows the hysteroscopic light to shine through the thinnest portion of myometrium at the apex of the isthmocele, whereas the near-infrared vision allowed by the da Vinci Firefly technology was used to precisely identify the borders of the defect. The carbon dioxide laser was used to completely remove the defect while avoiding damage to delicate reproductive tissue and over-excision. No complications were identified during the postoperative visit. Magnetic resonance imaging 3 months after the surgery revealed an RMT of 10 mm at the location of excision compared with the initial RMT of 1.4 mm. CONCLUSION(S): Currently, there is no gold-standard technique for surgical management of isthmocele. This is the first description of the combined use of hysteroscopy, near-infrared vision, and laser fiber for the robotic excision of isthmocele. This specific setup proves to be a useful technical improvement. The use of near-infrared vision combined with precise hysteroscopic targeting allows much clearer definition of he isthmocele borders, and the flexible laser fiber allows millimetric xcision in the absence of appreciable lateral thermal spread. Further investigation is warranted to identify a gold-standard surgical technique for patients with cesarean scar defect.

Ultra-low-dose and very-low-dose Lupron downregulation protocols for poor responders based on POSEIDON group 3 and 4 classifications.

PURPOSE: The objective of this study was to assess if very-low-dose Lupron (VLDL) and ultra-low-dose Lupron (ULDL) protocols can have comparable cycle outcomes when compared to other "poor responder" stimulation protocols based on POSEIDON classification groups 3 (PG3) and 4 (PG4). METHODS: A retrospective cohort study at a single, large academic center was performed. Women in PG3 (age < 35, AMH < 1.2 ng/mL) or PG4 (age ≥ 35, AMH < 1.2 ng/mL) undergoing in vitro fertilization using an ULDL (Lupron 0.1 to 0.05 mg daily), VLDL (Lupron 0.2 to 0.1 mg daily), microflare (Lupron 0.05 mg twice a day), estradiol priming/antagonist, antagonist, or minimal stimulation protocols from 2012 to 2021 were included. The primary outcome was the number of mature oocytes (MII) obtained. The secondary outcome was live birth rate (LBR). RESULTS: The cohort included 3601 cycles. The mean age was 38.1 ± 3.8 years. In the PG3 group, ULDL and VLDL protocols produced a comparable number of MIIs (5.8 ± 4.3 and 5.9 ± 5.4, respectively) and live births (33.3% and 33.3%, respectively) when compared to other protocols. In the PG4 group, ULDL and VLDL protocols resulted in a higher percentage of MIIs when compared to microflare or minimal stimulation (Microflare/ULDL: adjusted relative risk (aRR) 0.78 (95% CI 0.65, 0.95); min stim/ULDL: aRR 0.47 (95% CI 0.38, 0.58); microflare/VLDL: aRR 0.77 (95% CI 0.63, 0.95); min stim/VLDL: aRR 0.47 (95% CI 0.38, 0.95)). There were no significant differences in LBR. CONCLUSION: Dilute Lupron downregulation protocols have comparable outcomes to other poor responder protocols and are reasonable to use.

Geographic disparities in peripartum cardiomyopathy outcomes.

BACKGROUND: Cardiomyopathy causes more than a third of late postpartum pregnancy-related deaths in the United States, and racial disparities in outcomes among pregnant individuals with cardiomyopathy exist. Underlying community factors may contribute to disparities in peripartum cardiomyopathy outcomes. OBJECTIVE: This study aimed to identify the geographic distribution of and disparities in peripartum cardiomyopathy outcomes, hypothesizing that patients living in communities with higher social vulnerability may have worse outcomes. STUDY DESIGN: This was a retrospective cohort study of patients with peripartum cardiomyopathy per the National Heart, Lung, and Blood Institute definition from January 2000 to November 2017 at a single center, excluding those with a post office box address as a post office box address may not reflect the census tract in which a patient resides. Severe peripartum cardiomyopathy (vs less severe peripartum cardiomyopathy) was defined as ejection fraction <30%, death, intensive care unit admission, left ventricular assist device or implantable cardioverter defibrillator placement, or transplant. The US census tract for the patient's address was linked to the Centers for Disease Control and Prevention Social Vulnerability Index, a 0 to 1 scale of a community's vulnerability to external stresses on health, with higher values indicating greater vulnerability. The Social Vulnerability Index includes social factors divided into socioeconomic, household composition, minority status, and housing type and transportation themes. The Social Vulnerability Index and Social Vulnerability Index components were compared among patients by peripartum cardiomyopathy severity. RESULTS: Of 95 patients in the original cohort, 5 were excluded because of the use of a post office box address. Of the remaining 90 patients, 56 met severe peripartum cardiomyopathy criteria. At baseline, individuals with and without severe peripartum cardiomyopathy had similar ages, marital status, payor type, tobacco use, gestational age at delivery, and mode of delivery; however, individuals with severe peripartum cardiomyopathy were more likely to be Black (vs White) (59% vs 29%; P<.007) and less likely to recover ejection fraction (EF) to ≥55% by 12 months (36% vs 62%; P=.02) than individuals with less severe peripartum cardiomyopathy. Patients with severe peripartum cardiomyopathy were more likely to live in areas with a higher Social Vulnerability Index (0.51 vs 0.31; P=.002) and with more residents who were unemployed, impoverished, without a high school diploma, in single-parent households, of minority status, without a vehicle, and in institutionalized group quarters than patients with less severe peripartum cardiomyopathy. The median income was lower in communities of individuals with severe peripartum cardiomyopathy than in communities of individuals with less severe peripartum cardiomyopathy. CONCLUSION: Patients with severe peripartum cardiomyopathy outcomes were more likely to live in communities with greater social vulnerability than patients with less severe peripartum cardiomyopathy outcomes. To reduce disparities and maternal mortality rates, resources may need to be directed to socially vulnerable communities.

Aquaporins: New players in breast cancer progression and treatment response.

Aquaporins (AQPs) are a family of small transmembrane proteins that selectively transport water and other small molecules and ions following an osmotic gradient across cell plasma membranes. This enables them to regulate numerous functions including water homeostasis, fat metabolism, proliferation, migration, and adhesion. Previous structural and functional studies highlight a strong biological relationship between AQP protein expression, localization, and key biological functions in normal and cancer tissues, where aberrant AQP expression correlates with tumorigenesis and metastasis. In this review, we discuss the roles of AQP1, AQP3, AQP4, AQP5, and AQP7 in breast cancer progression and metastasis, including the role of AQPs in the tumor microenvironment, to highlight potential contributions of stromal-derived to epithelial-derived AQPs to breast cancer. Emerging evidence identifies AQPs as predictors of response to cancer therapy and as targets for increasing their sensitivity to treatment. However, these studies have not evaluated the requirements for protein structure on AQP function within the context of breast cancer. We also examine how AQPs contribute to a patient's response to cancer treatment, existing AQP inhibitors and how AQPs could serve as novel predictive biomarkers of therapy response in breast cancer. Future studies also should evaluate AQP redundancy and compensation as mechanisms used to overcome aberrant AQP function. This review highlights the need for additional research into how AQPs contribute molecularly to therapeutic resistance and by altering the tumor microenvironment.

Oocyte cryopreservation review: outcomes of medical oocyte cryopreservation and planned oocyte cryopreservation.

BACKGROUND: The utilization of oocyte cryopreservation (OC) has become popularized with increasing numbers of reproductive-aged patients desiring to maintain fertility for future family building. OC was initially used for fertility preservation in postmenarchal patients prior to gonadotoxic therapies; however, it is now available to patients to circumvent age-related infertility and other diagnoses associated with early loss of ovarian reserve. The primary aim of this paper is to provide a narrative review of the most recent and robust data on the utilization and outcomes of OC in both patient populations. OC results in similar oocyte yield in patients facing gonadotoxic therapies and patients undergoing planned OC. Available data are insufficient to predict the live birth rates or the number of oocytes needed to result in live birth. However, oocyte yield and live birth rates are best among patients < 37.5 years old or with anti-mullerian hormone levels > 1.995 ng/dL, at the time of oocyte retrieval. There is a high 'no use' rate (58.9%) in patients using planned OC with 62.5% returning to use frozen oocytes with a spouse. The utilization rate in medical OC patients is < 10%. There is currently no data on the effects of BMI, smoking, or ethnicity on planned OC outcomes. CONCLUSION: It is too early to draw any final conclusions on outcomes of OC in medical OC and planned OC; however, preliminary data supports that utilization of OC in both groups result in preservation of fertility and subsequent live births in patients who return to use their cryopreserved eggs. Higher oocyte yield, with fewer ovarian stimulation cycles, and higher live birth rates are seen in patients who seek OC at younger ages, reinforcing the importance of age on fertility preservation. More studies are needed in medical OC and planned OC to help guide counseling and decision-making in patients seeking these services.

The Effects of Antepartum Depressive Symptoms on Postcesarean Opioid Consumption.

OBJECTIVE: The study aimed to test the hypothesis that higher Edinburgh Postnatal Depression Scale (EPDS) scores are associated with increased pain scores and opioid use during postpartum hospitalization following cesarean section. STUDY DESIGN: We conducted a retrospective cohort of English or Spanish-speaking women ≥18 years who had prenatal care for a singleton gestation and delivered by cesarean at ≥36 weeks within a tertiary center during 2017. Exclusions included women with fetal anomalies, intrauterine fetal demise, sickle cell disease, previously diagnosed pain disorders (e.g., chronic pain or fibromyalgia), substance use disorder (based on documented prescription or use of methadone or buprenorphine), or reoperation during hospital stay. Women without an EPDS recorded antenatally were also excluded. Major depressive symptoms (MDS) were defined as a documented antenatal EPDS ≥12. Women with and without MDS were compared, and multivariable linear regression models were generated to evaluate associations between MDS status and both pain scores and opioid use. RESULTS: Of the 891 women meeting other inclusion criteria, 676 (76%) had documented antenatal EPDS scores, and 104 (15.4%) of those had MDS. Women with MDS were more likely to be use tobacco and have general anesthesia for cesarean delivery, but groups were otherwise similar. Women with MDS reported higher daily and average pain scores postpartum (2.4 vs. 1.7 average; p < 0.001). Women with MDS used more morphine milligram equivalents (MME) each day during their postpartum hospitalization, leading to a higher total MME use (121 mg [60.5-214.5] vs. 75 mg [28.5-133.5], p < 0.001). CONCLUSION: We found an association between antepartum depressive symptoms and acute pain after cesarean delivery leading to increased opioid use. Given the current focus on opioid stewardship, further research into this association, exploration of tailored pain control, and determining whether treatment of antepartum MDS reduces postpartum pain, and therefore opioid use, will be of the utmost priority. KEY POINTS: · Women with MDS report higher pain scores postcesarean.. · Women with MDS use more opioids postcesarean.. · Future studies are needed for the treatment of MDS..

Investigation of racial disparities in semen parameters among white, black, and Asian men.

BACKGROUND: Male factor infertility is the primary cause of infertility in 20% of couples. Primary evaluation of male factor infertility includes a semen analysis (SA). The World Health Organization (WHO) criteria are widely used to interpret SA. However, the current normative values seen in WHO criteria have led to research showing racial disparities in prevalence of abnormal SA. OBJECTIVE: To assess the relationship between different self-reported racial groups and rates of abnormal SA. MATERIALS & METHODS: We conducted a retrospective cohort study at a single large tertiary care facility. All men who underwent a SA for evaluation of suspected male infertility, unexplained infertility, intrauterine insemination, and in vitro fertilization between January 1, 2017 and December 31, 2019, were considered for inclusion in the study. Exclusion criteria were unreported race or ethnicity, SA for fertility preservation only, history of varicocele or testicular surgery, chromosomal abnormalities, congenital bilateral absence of vas deferens, prior testosterone use, or prior exposure to chemotherapy and/or radiation. Samples obtained via testicular sperm extraction or post-ejaculatory urine collection, or those analyzed ≥1 h from ejaculation, were also excluded. RESULTS: 872 SAs were identified, of which 615 met inclusion criteria, yielding 384 normal and 231 abnormal results. Only race (p < 0.0001) and age (p = 0.002) were statistically significant. Black men had the highest rate of abnormal SA (54%) and were significantly more likely to have lower semen volume, sperm concentration, total sperm count, percent motile sperm, and total motile sperm (p < 0.05). In a logistic regression model, controlling for age and using White Non-Hispanic as the referent group, only Blacks had lower odds for a normal SA (OR = 0.41, 95% CI 0.28, 0.60). DISCUSSION AND CONCLUSIONS: Black men are more likely to have an abnormal SA based on the 2010 WHO criteria. Black men seeking infertility treatment should be educated on the incidence of abnormal SA and actively seek infertility evaluation.

To treat or not to treat: perceptions of the initial American Society for Reproductive Medicine COVID-19 recommendations among women's health providers.

PURPOSE: The objective of this study was to evaluate the perception of the initial ASRM COVID-19 recommendations for infertility treatment held by women's health providers within varying subspecialties, as well as their attitudes toward pregnancy and fertility during this time. METHODS: An electronic survey was sent to all women's healthcare providers, including physicians, mid-level providers and nurses, in all subspecialties of obstetrics and gynaecology (Ob/Gyn) at a large tertiary care university-affiliated hospital. RESULTS: Of the 278 eligible providers, the survey response rate was 45% (n = 127). Participants represented 8 Ob/Gyn subspecialties and all professional levels. Participants age 18-30 years were significantly more likely to feel that women should have access to infertility treatment despite the burden level of COVID-19 in respective community/states (p = 0.0058). Participants within the subspecialties of general Ob/Gyn, maternal foetal medicine and gynecologic oncology were significantly more likely to disagree that all women should refrain from planned conception during the COVID-19 pandemic, in comparison to those in urogynecology and reproductive endocrinology and infertility (p = 0.0003). CONCLUSIONS: Considering the immediate and unknown long-term impact of the COVID-19 pandemic on fertility care delivery, a better understanding of perceptions regarding infertility management during this time is important. Our study shows overall support for the initial ASRM recommendations, representing a wide spectrum of women's health providers.

Exploiting Protein Translation Dependence in Multiple Myeloma with Omacetaxine-Based Therapy.

PURPOSE: The prognosis of patients with multiple myeloma who are resistant to proteasome inhibitors, immunomodulatory drugs (IMiD), and daratumumab is extremely poor. Even B-cell maturation antigen-specific chimeric antigen receptor T-cell therapies provide only a temporary benefit before patients succumb to their disease. In this article, we interrogate the unique sensitivity of multiple myeloma cells to the alternative strategy of blocking protein translation with omacetaxine. EXPERIMENTAL DESIGN: We determined protein translation levels (n = 17) and sensitivity to omacetaxine (n = 51) of primary multiple myeloma patient samples. Synergy was evaluated between omacetaxine and IMiDs in vitro, ex vivo, and in vivo. Underlying mechanism was investigated via proteomic analysis. RESULTS: Almost universally, primary patient multiple myeloma cells exhibit >2.5-fold increased rates of protein translation compared with normal marrow cells. Ex vivo treatment with omacetaxine resulted in >50% reduction in viable multiple myeloma cells. In this cohort, high levels of translation serve as a biomarker for patient multiple myeloma cell sensitivity to omacetaxine. Unexpectedly, omacetaxine demonstrated synergy with IMiDs in multiple myeloma cell lines in vitro. In addition, in an IMiD-resistant relapsed patient sample, omacetaxine/IMiD combination treatment resensitized the multiple myeloma cells to the IMiD. Proteomic analysis found that the omacetaxine/IMiD combination treatment produced a double-hit on the IRF4/c-MYC pathway, which is critical to multiple myeloma survival. CONCLUSIONS: Overall, protein translation inhibitors represent a potential new drug class for myeloma treatment and provide a rationale for conducting clinical trials with omacetaxine alone and in combination with IMiDs for patients with relapsed/refractory multiple myeloma.

Aquaporin-7 Regulates the Response to Cellular Stress in Breast Cancer.

The complex yet interrelated connections between cancer metabolism, gene expression, and oncogenic driver genes have the potential to identify novel biomarkers and drug targets with prognostic and therapeutic value. Here we effectively integrated metabolomics and gene expression data from breast cancer mouse models through a novel unbiased correlation-based network analysis. This approach identified 35 metabolite and 34 gene hubs with the most network correlations. These hubs have prognostic value and are likely integral to tumor metabolism and breast cancer. The gene hub Aquaporin-7 (Aqp7), a water and glycerol channel, was identified as a novel regulator of breast cancer. AQP7 was prognostic of overall survival in patients with breast cancer. In mouse breast cancer models, reduced expression of Aqp7 caused reduced primary tumor burden and lung metastasis. Metabolomics and complex lipid profiling of cells and tumors with reduced Aqp7 revealed significantly altered lipid metabolism, glutathione metabolism, and urea/arginine metabolism compared with controls. These data identify AQP7 as a critical regulator of metabolic and signaling responses to environmental cellular stresses in breast cancer, highlighting AQP7 as a potential cancer-specific therapeutic vulnerability. SIGNIFICANCE: Aquaporin-7 is identified as a critical regulator of nutrient availability and signaling that responds to cellular stresses, making it an attractive therapeutic target in breast cancer. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/19/4071/F1.large.jpg.

Measurement of ex vivo resistance to proteasome inhibitors, IMiDs, and daratumumab during multiple myeloma progression.

The oncogenic drivers and progression factors in multiple myeloma (MM) are heterogeneous and difficult to target therapeutically. Many different MM drugs have emerged, however, that attack various phenotypic aspects of malignant plasma cells. These drugs are administered in numerous, seemingly interchangeable combinations. Although the availability of many treatment options is useful, no clinical test capable of optimizing and sequencing the treatment regimens for an individual patient is currently available. To overcome this problem, we developed a functional ex vivo approach to measure patients' inherent and acquired drug resistance. This method, which we termed myeloma drug sensitivity testing (My-DST), uses unselected bone marrow mononuclear cells with a panel of drugs in clinical use, followed by flow cytometry to measure myeloma-specific cytotoxicity. We found that using whole bone marrow cultures helped preserve primary MM cell viability. My-DST was used to profile 55 primary samples at diagnosis or at relapse. Sensitivity or resistance to each drug was determined from the change in MM viability relative to untreated control samples. My-DST identified progressive loss of sensitivity to immunomodulatory drugs, proteasome inhibitors, and daratumumab through the disease course, mirroring the clinical development of resistance. Prospectively, patients' ex vivo drug sensitivity to the drugs subsequently received was sensitive and specific for clinical response. In addition, treatment with <2 drugs identified as sensitive by My-DST led to inferior depth and duration of clinical response. In summary, ex vivo drug sensitivity is prognostically impactful and, with further validation, may facilitate more personalized and effective therapeutic regimens.

Determining the Initiation of Opiate Misuse Resulting in Opioid Use Disorder in Pregnant Women.

The aim of this study was to explore the "opiate misuse footprint" made by obstetrics and gynecology physicians in prescribing opioid medications for postpartum pain control that led to opioid misuse and opioid use disorder. Data were collected using intake information and anonymous surveys administered to pregnant women at local methadone clinics in Indianapolis, Indiana, in 2016-2017. Results from this study revealed that 40% of the 33 participants stated that the first drug they became addicted to was prescription opioids; 71% stated that the first opiate they became addicted to was a prescription pain medication. Prescription opioids were mainly obtained from emergency medicine physicians and friends. Reported use of opioids within the past four months was high, with the most commonly used drugs being methadone (57.6%) and heroin (42.4%). A majority of participants also endorsed a history of sexual and physical abuse, recent incarceration, and mental health disorders. As a large number of pregnant women with opioid use disorder reported their initial drug of misuse as prescription pain medications, it is important to avoid overprescribing opioids in reproductive-age women.

Highly sensitive sequence specific qPCR detection of Mycobacterium tuberculosis complex in respiratory specimens.

Nucleic acid amplification tests for Mycobacterium tuberculosis (MTB) detection from sputum are highly sensitive and specific with smear microscopy positive specimens, but their sensitivity with smear-negative/culture-positive specimens is much lower; therefore, these tests cannot rule out a tuberculosis diagnosis. Co-extraction of PCR inhibitors may be a cause of decreased test sensitivity. Here the design and early validation of a MTB screening assay with sample preparation and qPCR methods designed to specifically address this diagnostic gap is reported. First, human genomic DNA is identified as a significant qPCR inhibitor. To circumvent this problem, a novel, streamlined sample preparation method utilizing detergent and proteolysis to thin the sputum and DNA sequence specific MTB DNA isolation was developed. Additionally, a multiplexed qPCR assay targeting two MTB complex-specific loci: the potentially multi-copy IS6110 and the single-copy senX3-regX3, combined with the cotJC gene from Bacillus atrophaeus spores amplified as a process control was developed. The limit of detection of the test was estimated to be 20 cfu/ml which is significantly lower than the Xpert® MTB/RIF assay. In a preliminary field study of 60 de-identified blinded sputa, a test sensitivity of 96% and specificity of 100% was observed when compared to the Xpert® MTB/RIF assay.