Transient expression analysis of promoters of okra enation leaf curl virus in Nicotiana benthamiana, cotton and okra plants.

Viral promoters can be used to drive heterologous gene expression in transgenic plants. As part of our quest to look for new promoters, we have explored, for the first time, the promoters of okra enation leaf curl virus (OELCuV), a begomovirus infecting okra (Abelmoschus esculentus). The Rep and CP promoters of OELCuV fused with the gfp reporter gene, were expressed transiently in the natural host okra and the laboratory host cotton and Nicotiana benthamiana. The expression levels of the promoters were quantified through confocal laser scanning microscopy and GFP assay in N. benthamiana and okra. The results indicated that the Rep promoter was more active than the CP promoter, whose activity was similar to that of CaMV 35S promoter. Additionally, the Rep and CP promoters showed increase of expression, probably due to transactivation, when assayed following inoculation of OELCuV and betasatellite DNAs in cotton plants. A moderate increase in promoter activity in N. benthamiana was also seen, when assayed following the inoculation of the heterologous begomovirus Sri Lankan cassava mosaic virus.

Multicystic renal dysplasia, a histomorphological spectrum: Seven years experience from a tertiary care hospital.

OBJECTIVES: Multicystic dysplastic kidney (MCDK) is defined as the presence of multiple noncommunicating cysts of various sizes, detected sonographically, without evidence of functioning renal parenchyma on dimercaptosuccinic acid renal scan. It has an incidence of 1:4000 live births. They are more commonly diagnosed in boys, usually on the left side, but may also be bilateral. There is the presence of primitive ducts surrounded by fibromuscular connective tissue. These are because of the disturbed connection of the ureteric bud with renal blastema and abnormal division at the stage of metanephros, resulting in an abnormal metanephros differentiation. MATERIALS AND METHODS: Thirty cases of MCDK were included to study their histomorphology along with their clinical features. Cases were retrieved from the last seven years (2015-2021) from the Department of Pathology, Maulana Azad Medical College. RESULT: Age ranged from 10 days to 18 years. The cases were between 1 years and 5 years of age. Six out of 30 cases (20%) were infants with three of them being neonates. Twenty-one cases were males. All the cases had unilateral kidney involvement with the left kidney being involved in 20 out of 30 cases. Twenty-eight cases underwent nephrectomy in view of small contracted nonfunctional kidneys with one of them being horseshoe shaped. Five cases had associated hydronephrosis (two ipsilateral and three bilateral). One case had Hirshprung's disease, four had anorectal malformation, two had posterior urethral valves with vesicourethral reflux, one had duplex moiety, and one had undescended testes. On histopathological examination, all of them showed the presence of immature disorganized tubules surrounded by a collarette of immature mesenchymal stroma. One of the cases showed osteoid formation and four had areas of immature cartilage. Normal kidney parenchyma was seen at the periphery in four cases. CONCLUSION: This series has been presented to highlight the various histomorphological features of MCDK. MCDK can be managed conservatively in most of cases due to autoinvolution and, hence, needs to be differentiated from other close differentials like polycystic kidney disease, cystic nephroma, and cystic partially differentiated nephroblastoma in order to avoid unnecessary surgical intervention.

Diffuse large B-cell lymphoma involving osseous sites: utility of response assessment by PET/CT and good longterm outcomes.

Osseous involvement by diffuse large B-cell lymphoma (DLBCL-bone) is a heterogeneous disease. There is limited data regarding response assessment by positron emission tomography with fluorodeoxyglucose, which may demonstrate residual avidity despite a complete response. We analyzed clinical data of patients with newly diagnosed DLBCL and identified all cases with DLBCL-bone. End of treatment scans were reviewed by two independent experts classifying osseous lesions into Deauville (DV) ≤3; DV ≥4, or reactive uptake in the bone marrow (M), site of fracture (F) or surgery (S). We compared outcomes of DLBCL-bone to other extranodal sites (EN) matched on International Prognotic Index features and regimen. Of 1,860 patients with DLBCL (bone 16%; EN 45%; nodal 39%), 41% had localized disease and 59% advanced. Only 9% (n=27) of patients with initial bone involvement had residual fluorodeoxyglucose avidity at the osseous site. In half of these cases, the uptake was attributed to F/S/M, and of the remaining 13, only two were truly refractory (both with persistent disease at other sites). Overall survival and progression-free survival (PFS) were found to be similar for early- stage nodal DLBCL and DLBCL-bone, but inferior in EN-DLBCL. Advanced-stage disease involving the bone had a similar 5-year PFS to nodal disease and EN-DLBCL. After matching for International Prognotic Index and treatment regiments, PFS between bone and other EN sites was similar. Osseous involvement in DLBCL does not portend a worse prognosis. End of treatment DV ≥4 can be expected in 5-10% of cases, but in the absence of other signs of refractory disease, may be followed expectantly.

Blood-stage antimalarial activity, favourable metabolic stability and in vivo toxicity of novel piperazine linked 7-chloroquinoline-triazole conjugates.

The persistence of drug resistance poses a significant obstacle to the advancement of efficacious malaria treatments. The remarkable efficacy displayed by 1,2,3-triazole-based compounds against Plasmodium falciparum highlights the potential of triazole conjugates, with diverse pharmacologically active structures, as potential antimalarial agents. We aimed to synthesize 7-dichloroquinoline-triazole conjugates and their structure-activity relationship (SAR) derivatives to investigate their anti-plasmodial activity. Among them, QP11, featuring a m-NO2 substitution, demonstrated efficacy against both chloroquine-sensitive and -resistant parasite strains. QP11 selectively inhibited FP2, a cysteine protease involved in hemoglobin degradation, and showed synergistic effects when combined with chloroquine. Additionally, QP11 hindered hemoglobin degradation and hemozoin formation within the parasite. Metabolic stability studies indicated high stability of QP11, making it a promising antimalarial candidate. In vivo evaluation using a murine malaria model demonstrated QP11's efficacy in eradicating parasite growth without neurotoxicity, presenting it as a promising compound for novel antimalarial development.

Developmental Abnormalities of the Pediatric Spine: A Review of the Correlation Between Ultrasound and MRI Findings.

A broad spectrum of spinal pathologies can affect the pediatric population. Ultrasound (US) is the primary modality for pediatric spine assessment due to its widespread availability, non-requirement of sedation, and absence of ionizing radiation. Supplementing this, MRI offers an in-depth exploration of these conditions, aiding in preoperative strategizing. In this review, we examine the clinical indications, methodologies, and protocols for US and MRI scans of the pediatric spine. Additionally, we illustrate normal pediatric spinal anatomy, highlighting several examples of normal variants that are often misinterpreted. Through a series of case-based illustrations, we offer a comprehensive overview of various pathological conditions such as tethered cord, spinal dysraphism, spinal lipoma, diastematomyelia, and dermal sinus tract, among others. Furthermore, we explore the correlation between US and MRI findings for these lesions, employing real-world cases to enhance our understanding of this topic.

Comparison of circulating tumor DNA between African American and Caucasian patients with metastatic castrate-resistant prostate cancer post-abiraterone and/or enzalutamide.

BACKGROUND: African American men are much more likely than Caucasian men to be diagnosed with and to die of prostate cancer. Genetic differences likely play a role. The cBioPortal database reveals that African American men with prostate cancer have higher rates of CDK12 somatic mutations compared to Caucasian men. However, this does not account for prior prostate cancer treatments, which are particularly important in the castrate-resistant setting. We aimed to compare somatic mutations based on circulating tumor DNA (ctDNA) in metastatic castration-resistant prostate cancer (mCRPC) between African American and Caucasian men after exposure to abiraterone and/or enzalutamide. METHODS: This single-institution retrospective study characterizes the somatic mutations detected on ctDNA for African American and Caucasian men with mCRPC who had progressed after abiraterone and/or enzalutamide from 2015 through 2022. We evaluated the gene mutations and types of mutations in this mCRPC cohort. RESULTS: There were 50 African American and 200 Caucasian men with CRPC with available ctDNA data. African American men were younger at the time of diagnosis (p = 0.008) and development of castration resistance (p = 0.006). African American men were more likely than Caucasian men to have pathogenic/likely pathogenic (P/LP) mutations in CDK12 (12% vs. 1.5%; p = 0.003) and copy number amplifications and P/LP mutations in KIT (8.0% vs. 1.5%; p = 0.031). African American men were also significantly more likely to have frameshift mutations (28% vs. 14%; p = 0.035). CONCLUSIONS: Compared to Caucasian men, African American men with mCRPC after exposure to abiraterone and/or enzalutamide had a higher incidence of somatic CDK12 P/LP mutations and KIT amplifications and P/LP mutations based on ctDNA. African American men also had more frameshift mutations. We hypothesize that these findings have potential implications for tumor immunogenicity.

Outcomes of Patients with Positive Interim Positron Emission Tomography (PET) Continuing ABVD in the Clinical Setting.

Recent prospective clinical trial data suggest that patients with Hodgkin's lymphoma who continue treatment with ABVD, despite failing to attain a complete metabolic response on interim PET (PET2+), may fare better than previously published. We describe the outcomes of PET2+ patients who continued ABVD and compare the performance of a quantitative measure based on the lesion-to-liver SUV ratio (LLS qPET2+) to that of the subjective Deauville criteria (dvPET2+). We analyzed all patients with newly diagnosed advanced-stage Hodgkin lymphoma treated with frontline ABVD at the Memorial Sloan Kettering Cancer Center between 2008 and 2017. Eligibility was set to correspond with the RATHL inclusion criteria. Images were reviewed by two nuclear medicine physicians and discordant cases were resolved with a third expert in consensus. qPET2+ was defined as LLS ≥ 1.3. We identified 227 patients of whom 25% (57) were qPET2+, but only 14% (31) were dvPET2+. Forty-eight patients (84%) continued ABVD with a 3-year PFS of 70% for qPET2+ and 64% for dvPET2+. In conclusion, interim PET interpretation in clinical practice may be associated with a higher rate of scans deemed positive. Irrespective of the criteria for PET2 positivity, a subset of patients may continue ABVD without a dismal outcome.

Congenital Pulmonary Airway Malformation - A Histomorphological Spectrum of 15 Cases: A 5-Year Study from a Tertiary Care Center.

OBJECTIVE: Congenital pulmonary airway malformation (CPAM) is a rare developmental lung disease. The aim of this study is to analyze the histomorphological spectrum of CPAM in a series of 15 cases. MATERIALS AND METHODS: A retrospective descriptive study of 15 cases of CPAM was carried out from 2013 to 2018 in our hospital, and cases were classified based on the Stocker's classification. RESULTS: The age ranged from 4 days to 9 years (66.6% were infants). The left lung was most commonly involved (66.6%). The most common lobe was the left upper lobe (60%), followed by right lower lobe (20%). Grossly, cysts measured 0.2-5 cm, filled with mainly serous fluid with few having hemorrhagic and brownish mucoid secretions. On microscopy, single to multiple noncommunicating cysts of size 0.2-5 cm were seen, lined by ciliated columnar epithelium (60%), pseudostratified ciliated columnar epithelium (26.7%), mucin-secreting columnar epithelium (6.7%), and flattened epithelium (6.7%). Few cases showed smooth muscle (20%) and cartilage (13.3%) in the cyst wall. Chronic inflammation (73.3%) with dense histiocytic infiltrate (13.3%) was also seen. Emphysematous changes were also observed (13.3%). Cytomegalovirus inclusions (6.7%), zygomycete fungus (6.7%), and red hepatization (6.7%) were observed. The most common type was type II (60%), followed by type I (33.3%) and type IV (6.7%). CONCLUSION: Type II was the most common variant in this study. A careful observation should be done to look for fungal hyphae or viral inclusions.

Papillary Tumor of Pineal Region in a 5-Year-Old Male Child: A Rare Entity.

Papillary tumor of the pineal region (PTPR) is a rare grade II to III pineal lesion. These tumors mostly occur in adults, only rarely in children, with six cases in children under the age of 16 years (10.2%) up to now. We report the case of a 5-year-old male child presenting with worsening headaches, abnormally enlarged head since birth and visual disturbances. Imaging reveals a mass in the region of the pineal gland. The third and lateral ventricles were enlarged. The patient underwent a gross-total surgical resection of pineal mass through a suboccipital supracerebellar approach and tissue sent for histopathological examination and an available immunohistochemical workup has been done which confirmed the diagnosis of papillary tumor pineal region. This case highlights the histopathological features, imaging along clinical presentation similar to those in the original description of this rare entity PTPR. More studies are required to determine the prognosis and standard treatment protocol of this rare entity.

Risk Factors and Outcomes During a First Acute Myocardial Infarction in Breast Cancer Survivors Compared with Females Without Breast Cancer.

PURPOSE: The purpose of this research was to study the differences in epidemiology and outcomes of a first myocardial infarction in breast cancer survivors compared with the general female population in the United States. METHODS: We retrospectively analyzed the US National Inpatient Sample years 2005-2015 to identify adult women with a first myocardial infarction. In this cohort, breast cancer survivors were identified. Outcomes evaluated were the differences in baseline demographics, comorbidities, and adjusted in-hospital mortality in women with and without breast cancer. RESULTS: Among 1,644,032 first myocardial infarction cases in adult women, there were 56,842 (3.5%) breast cancer survivors. Compared with women without breast cancer, breast cancer survivors were 6 years older (mean age 77 vs 71 years, P < .001), had significantly higher prevalence of dyslipidemia and hypertension, and lower prevalence of obesity, diabetes mellitus, and smoking. Breast cancer survivors were more likely to have a non-ST segment elevation acute myocardial infarction and less likely to receive mechanical revascularization. In-hospital mortality was lower in breast cancer survivors (7.1%) compared with those without (7.9%, P < .001), findings that persisted after risk adjustment (odds ratio 0.89; 95% CI, 0.82-0.94). CONCLUSIONS: Breast cancer survivors had a first acute myocardial infarction at an older age and had small but favorable differences in cardiovascular disease risk factors and outcomes compared with women without breast cancer. The favorable impact of health education, preventative medical care, greater motivation for a healthier lifestyle, and participation in cancer survivorship programs on these seemingly paradoxical findings in breast cancer survivors should be further explored.

Sonographic features of invasive ductal breast carcinomas predictive of malignancy grade.

CONTEXT: Assessment of individual sonographic features provides vital clues about the biological behavior of breast masses and can assist in determining histological grade of malignancy and thereby prognosis. AIMS: Assessment of individual sonographic features of biopsy proven invasive ductal breast carcinomas as predictors of malignancy grade. SETTINGS AND DESIGN: A retrospective analysis of sonographic findings of 103 biopsy proven invasive ductal breast carcinomas. MATERIALS AND METHODS: Tumor characteristics on gray-scale ultrasound and color flow were assessed using American College of Radiology (ACR) Breast Imaging Reporting and Data System (BI-RADS) Atlas Fifth Edition. The sonographic findings of masses were individually correlated with their histopathologic grades. STATISTICAL ANALYSIS USED: Chi square test, ordinal regression, and Goodman and Kruskal tau test. RESULTS: Breast mass showing reversal/lack of diastolic flow has a high probability of belonging to histological high grade tumor (ß 1.566, P 0.0001). The masses with abrupt interface boundary are more likely grade 3 (ß 1.524, P 0.001) in comparison to masses with echogenic halos. The suspicious calcifications present in and outside the mass is a finding associated with histologically high grade tumors. The invasive ductal carcinomas (IDCs) with complex solid and cystic echotexture are more likely to be of high histological grade (ß 1.146, P 0.04) as compared to masses with hypoechoic echotexture. CONCLUSIONS: Certain ultrasound features are associated with tumor grade on histopathology. If the radiologist is cognizant of these sonographic features, ultrasound can be a potent modality for predicting histopathological grade of IDCs of the breast, especially in settings where advanced tests such as receptor and molecular analyses are limited.

Characterization of Differences Between Prostate Cancer Patients Presenting With De Novo Versus Primary Progressive Metastatic Disease.

BACKGROUND: Men who present with metastatic disease can have de novo or primary progressive disease. We characterized and compared the outcomes between these 2 groups. PATIENTS AND METHODS: A retrospective cross-sectional analysis from a single institution of de novo versus primary progressive metastatic patients during a 2-year consecutive period was undertaken. Patient characteristics such as demographics, Gleason score, duration of hormone sensitivity, and treatment were obtained. The t test, Mann-Whitney U test, and Fisher exact test were used to test differences in patient and disease characteristics between the de novo and primary progressive metastatic groups. Differences in the Kaplan-Meier survival curves were compared using the log-rank test. RESULTS: A total of 90 patients (n = 38 with de novo and 52 with primary progressive disease) were included. Statistically significant median differences were found for the prostate-specific antigen level at the development of metastases: de novo 63.1 ng/ml vs primary progressive 12.5 ng/ml, p= <.001; albumin and hemoglobin, P = .03 and P = .045, respectively). The median duration of hormone sensitivity was 372 days (range, 54-3753 days) in the de novo group versus 1613 days (range, 7-4314 days) in the primary progressive group (P = .00006). Overall survival was worse in the de novo arm, with a median survival of 6.2 years compared with a median survival in the primary progressive group of 11.6 years (P = .027). CONCLUSION: Although the reported samples were small, our data revealed a potential difference in disease aggressiveness in those presenting with de novo metastatic cancer with higher risk disease and shorter time to castration resistance and worse survival. These data could have implications for earlier and more aggressive treatment for men presenting with de novo metastatic prostate cancer.

Long-term Results of Post-operative Pelvic Image guided Intensity Modulated Radiotherapy in Gynecological Malignancies.

OBJECTIVE: To assess late clinical outcomes with image guided intensity modulated radiotherapy (IG- IMRT) in gynecological malignancies. PATIENTS AND METHODS: We have been practicing IG IMRT for gynecological malignancies since January 2009. Here we are presenting our experience with this modern technique at median follow up of 38 months. During whole treatment bladder filling protocol was followed. Both target volumes and critical structures were contoured according to RTOG guidelines. Dose prescribed to clinical target volume (postop bed and nodal volume) was 50.4 Gy in 28 fractions. Cone beam CT (CBCT) scans were taken to quantify the status of target volume and normal structures. RESULTS: 80 patients were evaluated and analyzed who were treated from January 2009 to December 2014. Median age of our patients was 56.5 years. Out of eighty, forty four patients (55%) were of carcinoma endometrium and the rest 36 (45%) were of carcinoma cervix. None of our patients experienced late grade 3 or 4 bladder toxicity. Although late grade 3 and 4 bowel and rectal toxicity was experienced by single patient. 2.5% patients developed local recurrence, 5% patient developed nodal with distant metastases and 6.25% only distant metastases. Three of our patients developed lung cancer as second primary during follow up. 76.2% atients are alive with regular follow up. CONCLUSIONS: Our study concluded that IG IMRT increases patient compliance and reduces long-term side effects in post-operative gynecological malignancies without compromising local-regional control, disease free survival and overall survival.

Double non coronary aortic sinuses: an autopsy case finding showing the arterial variation / Senos aórticos dobles, no coronarios: un caso de autopsia que demuestra la variación arterial

We report a case of variant origin of the right coronary artery from the left posterior aortic sinus. This was observed routinely during a medico legal autopsy of a 58 year old male who died in a road traffic accident. Initially it was believed that the right coronary artery was absent since there was no obvious right coronary artery ostium from the anterior aortic sinus. However it was found later that the right coronary ostium was present just beside the left coronary ostium in the left posterior aortic sinus and the right coronary artery was arising from the left posterior aortic sinus. The right coronary artery had an intramural course between the aorta and pulmonary trunk, which is considered as very dangerous and life threatening. We believe that the present case report will be enlightening to the cardiologist and cardiothoracic surgeon. It is also true that the conduction of medico legal autopsies of coronary arteries is important for the medico legal resolution.

Se presenta un caso de variación de origen de la arteria coronaria derecha desde el seno aórtico posterior izquierdo. Esto se observó de forma rutinaria durante una autopsia médico-legal de un hombre de 58 años que murió en un accidente de tránsito. Inicialmente se creía que la arteria coronaria derecha estaba ausente ya que no había un ostium observable desde el seno aórtico anterior. Sin embargo, se descubrió más tarde que el ostium de la arteria coronaria derecha estaba presente justo al lado del ostium de la arteria coronaria izquierda en el seno aórtico posterior izquierdo y la arteria coronaria derecha se originaba del seno aórtico posterior izquierdo. La arteria coronaria derecha presentó un recorrido intramural entre la aorta y el tronco pulmonar, que se considera como muy peligroso y potencialmente mortal. Creemos que el presente trabajo será esclarecedor para el cardiólogo y el cirujano cardiotorácico. También consideramos que el conocimiento de la anatomía de las arterias coronarias es importante durante el desarrollo de la autopsia médico-legal para lograr alcanzar una correcta resolución del proceso medicolegal.

Case of CML lymphoid blast crisis presenting as bilateral breast masses.

A woman aged 42 years with a 1-month history of rapidly expanding bilateral breast masses presented with severe leucocytosis, anaemia, blurry vision, headaches and shortness of breath. Evaluation revealed chronic myeloid leukaemia in lymphoid blast crisis with extramedullary leukaemia involving her breasts.

The promising role of nivolumab in renal cell cancers.

The therapeutic efficacy of checkpoint inhibitors across numerous tumor types has resulted in approval for neoplasms such as melanoma and lung cancer. Nivolumab is a fully humanized IgG4 antibody that inhibits immune checkpoint between programmed death 1 (PD-1) on T cells and PD-1 ligand 1 (PD-L1) and ligand 2 (PD-L2) on immune and cancer cells. Motzer and Colleagues published the findings of Nivolumab versus everolimus in advanced kidney cancer in the November issue of the New England Journal of Medicine. This trial showed that nivolumab resulted in better median overall survival of 25 months compared to everolimus at 19.6 months, with a hazard ratio for death at 0.73, meeting pre-specified criterion for superiority in favor of nivolumab. These findings mark the defining beneficial role of immune checkpoint inhibitor therapy in metastatic kidney cancer.

The Utility of Chemotherapy in the Treatment of Metastatic Prostate Cancer.

Prostate cancer is the most common cancer among American men and the second most common cause of cancer deaths among men. Treatment of prostate cancer remains a challenge. Despite decades of research, few cytotoxic chemotherapy agents have shown promise against prostate cancer. In this paper, we will discuss the history of chemotherapy in prostate cancer, the pivotal trials with docetaxel that advanced the field, the cytotoxic chemotherapy agents, including cabazitaxel, as well as combination therapy with docetaxel or cabazitaxel and the potential implications of biomarkers such as AR-V7 in chemotherapy use.

A synopsis of drugs currently in preclinical and early clinical development for the treatment of benign prostatic hyperplasia.

INTRODUCTION: Benign prostatic hyperplasia (BPH) is a common disease among men and significantly impacts quality of life by causing lower urinary tract symptoms (LUTS). Current medical therapies are not always adequate in controlling LUTS or slowing disease progression, and there is unmet need for new effective therapeutic options. AREAS COVERED: The authors review the standard current medical therapies for BPH which include the use of α-1 blockers, 5-α reductase inhibitors, combination therapy and PDE inhibitors. Following this, the authors then discuss new therapies that are currently undergoing preclinical and clinical investigation. EXPERT OPINION: Existing preclinical and clinical trials have highlighted many promising therapies to treat BPH. Further investigation with larger clinical trials is needed to establish these drugs as standard therapies. As the number of drugs in the arsenal against BPH continues to grow, providers and patients will have to engage in a discussion that weighs the risks and benefits of each therapy.

Targeting nodal in conjunction with dacarbazine induces synergistic anticancer effects in metastatic melanoma.

UNLABELLED: Metastatic melanoma is a highly aggressive skin cancer with a poor prognosis. Despite a complete response in fewer than 5% of patients, the chemotherapeutic agent dacarbazine (DTIC) remains the reference drug after almost 40 years. More recently, FDA-approved drugs have shown promise but patient outcome remains modest, predominantly due to drug resistance. As such, combinatorial targeting has received increased attention, and will advance with the identification of new molecular targets. One attractive target for improving melanoma therapy is the growth factor Nodal, whose normal expression is largely restricted to embryonic development, but is reactivated in metastatic melanoma. In this study, we sought to determine how Nodal-positive human melanoma cells respond to DTIC treatment and to ascertain whether targeting Nodal in combination with DTIC would be more effective than monotherapy. A single treatment with DTIC inhibited cell growth but did not induce apoptosis. Rather than reducing Nodal expression, DTIC increased the size of the Nodal-positive subpopulation, an observation coincident with increased cellular invasion. Importantly, clinical tissue specimens from patients with melanomas refractory to DTIC therapy stained positive for Nodal expression, both in pre- and post-DTIC tumors, underscoring the value of targeting Nodal. In vitro, anti-Nodal antibodies alone had some adverse effects on proliferation and apoptosis, but combining DTIC treatment with anti-Nodal antibodies decreased cell growth and increased apoptosis synergistically, at concentrations incapable of producing meaningful effects as monotherapy. IMPLICATIONS: Targeting Nodal in combination with DTIC therapy holds promise for the treatment of metastatic melanoma.