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In the article cited above, the affiliations for authors Stephen J. Pandol and Maike Sander were inadvertently transposed. The correct affiliation for Stephen J. Pandol is Department of Gastroenterology, Cedars-Sinai Medical Center, Los Angeles, CA. The correct affiliation for Maike Sander is Department of Pediatrics and Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA. The online version of the article (https://doi.org/10.2337/db22-0942) has been updated with the correct affiliations.

Figure S1. In vitro optimization of iRGD TPNs in PDAC cell lines; Figure S2. Dual knockdown using TPNs; Figure S3. In vitro and in vivo properties and function of PEGylated iRGD TPNs; Figure S4. Overview of organoid image analysis; Figure S5. iRGD TPN-mediated delivery of siRNA in models of pancreatic cancer; Figure S6. iRGD-mediated TPN uptake and NRP-1 expression in the tumor vasculature; Figure S7. Stromal elements in a KPC-derived orthotopic tumor section following iRGD TPN administration.

Pancreatic cancer is one of the leading causes of cancer-related death, with 5-year survival of 8.5%. The lack of significant progress in improving therapy reflects our inability to overcome the desmoplastic stromal barrier in pancreatic ductal adenocarcinoma (PDAC) as well as a paucity of new approaches targeting its genetic underpinnings. RNA interference holds promise in targeting key mutations driving PDAC; however, a nucleic acid delivery vehicle that homes to PDAC and breaches the stroma does not yet exist. Noting that the cyclic peptide iRGD mediates tumor targeting and penetration through interactions with αvβ3/5 integrins and neuropilin-1, we hypothesized that “tandem” peptides combining a cell-penetrating peptide and iRGD can encapsulate siRNA to form tumor-penetrating nanocomplexes (TPN) capable of delivering siRNA to PDAC. The use of directly conjugated iRGD is justified by receptor expression patterns in human PDAC biopsies. In this work, we optimize iRGD TPNs with polyethylene glycol (PEG)-peptide conjugates for systemic delivery to sites of disease. We show that TPNs effectively knockdown siRNA targets in PDAC cell lines and in an immunocompetent genetically engineered mouse model of PDAC. Furthermore, we validate their tumor-penetrating ability in three-dimensional organoids and autochthonous tumors. In murine therapeutic trials, TPNs delivering anti-Kras siRNA significantly delay tumor growth. Thus, iRGD TPNs hold promise in treating PDAC by not only overcoming physical barriers to therapy, but by leveraging the stroma to achieve knockdown of the gold-standard genetic target. Moreover, the modular construction of this delivery platform allows for facile adaptation to future genetic target candidates in pancreatic cancer. Mol Cancer Ther; 17(11); 2377–88. ©2018 AACR.

Intravital imaging of a subcutaneous pancreatic cancer xenograft (MIA PaCa-2) showing distribution of PEGylated iRGD TPNs (green) in tumor cell compartments surrounding abnormal tumor blood vessels. Collagen visualized through second-harmonic generation is displayed in magenta. Images in this video were captured at a depth of 60 μm from the edge of the exposed tumor. Each frame of 0.25 sec represents 5 min of elapsed time, starting 3 minutes after injection of the particles. Please refer to Figure S5 for reference scale bar.

The oligomeric organization of membrane proteins in native cell membranes is a critical regulator of their function. High-resolution quantitative measurements of oligomeric assemblies and how they change under different conditions are indispensable to the understanding of membrane protein biology. We report a single-molecule imaging technique (Native-nanoBleach) to determine the oligomeric distribution of membrane proteins directly from native membranes at an effective spatial resolution of ∼10 nm. We achieved this by capturing target membrane proteins in “native nanodiscs” with their proximal native membrane environment using amphipathic copolymers. We established this method using structurally and functionally diverse membrane proteins with well-established stoichiometries. We then applied Native-nanoBleach to quantify the oligomerization status of a receptor tyrosine kinase (TrkA) and a small GTPase (KRas) under conditions of growth-factor binding or oncogenic mutations, respectively. Native-nanoBleach provides a sensitive, single-molecule platform to quantify membrane protein oligomeric distributions in native membranes at an unprecedented spatial resolution.

Human epidemiologic studies support a strong link between increased pancreatic adenocarcinoma (PDAC) risk and high fat diet (HFD) consumption, obesity, and overall energy imbalance. Given the rapid rise in worldwide obesity rates and the prevalence of western diets rich in fat, deciphering these mechanisms is not only a societal imperative but also represents a key untapped target to develop novel strategies for prevention and therapy. The translational relevance of diet research, however, has been limited by inconsistencies in fat source and consumption across human populations and mouse studies. Therefore, whether and how specific dietary fatty acids drive cancer development is poorly understood. To identify commonly consumed dietary fats capable of promoting pancreatic tumorigenesis, we fed a novel panel of 12 isocaloric HFDs – differing solely in fat source and representing the diversity of modern human fat consumption (as per statistics from the USDA) – to an oncogenic Kras-driven mouse model (KC: Pdx1-Cre; KrasLSL-G12D/+) that closely mimics the genetic and histologic features of human PDAC progression. Surprisingly, we found that diets rich in oleic acid (OA), a monounsaturated fat typically associated with good health, were strongly correlated with enhanced precancerous pancreatic intraepithelial neoplasia (PanIN) formation, arguing that OA enhances Kras-induced cellular transformation and early progression. High-oleic diets (HODs) and OA treatment of primary acinar cells induced loss of acinar cell identity and acquisition of ductal markers, consistent with a direct role for OA in acinar-to-ductal metaplasia (ADM), a prerequisite step in early PDAC development. Lipidomic analyses of plasma, liver, and muscle of mice fed HODs revealed greater circulating OA levels and increased tissue incorporation of OA into the acyl chains of phospholipids and sphingolipids, which make up the plasma membrane of cells and mediate intracellular and extracellular signaling. Furthermore, plasma and tissue OA levels more strongly correlated with tumor development, suggesting that direct OA pancreatic tissue incorporation could drive tumorigenesis. Indeed, molecular and biochemical analyses confirmed upregulation in the expression of de novo lipogenesis genes, alterations in lipid metabolism, and enhanced mTOR signaling in pancreata of mice fed HODs. Overall, these results directly link dietary OA to pancreatic lipid metabolism and transformation during PDAC development and highlight the complex pleiotropic effects of dietary fatty acids on health and disease: OA, while beneficial for heart health, may promote the development of certain cancers, such as PDAC. Uncovering the links between specific dietary fats and tumorigenesis are critical to enable precision nutritional guidance for the prevention and treatment of PDAC and potentially other obesity-associated cancers. Citation Format: Christian F. Ruiz, Rylee McDonnell, Jennifer Kaplan, Jasper de Jong, Christine Shugrue, Michael C. Rudolph, Fred S. Gorelick, John Wysolmerski, Matthew Rodeheffer, Mandar D. Muzumdar. Excess dietary oleic acid primes the pancreas for cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr PR015.

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death in the United States. Various epidemiologic studies have shown that obesity increases the risk of PDAC. With rising rates of obesity worldwide, it is imperative that we understand the mechanisms by which obesity promotes PDAC progression. Therefore, to study the effect of obesity on PDAC, we combined a well-established genetic model of obesity (Lepob/ob) with a faithful oncogenic Kras-driven pancreatic cancer model (KC: Pdx1-Cre; KrasLSL-G12D/+) and showed that obese mice had both increased tumor burden and shortened survival compared to their lean counterparts. Strikingly, weight loss (via AAV-leptin rescue or caloric restriction), decreased tumor development, demonstrating that the tumor-promoting effects of obesity can be reversed. Bulk-RNA sequencing of tumors from obese mice exhibited aberrant expression of islet beta-cell genes, including those coding for the peptide hormones cholecystokinin (CCK) and amylin (Iapp). Single-cell RNA sequencing of islet beta-cells from wild-type, high fat diet-fed, and Lepob/ob mice revealed a trajectory of beta-cell adaptation to obesity with dysregulated hormone expression, including downregulation of insulin expression and upregulation of CCK and Iapp, concordant with loss of beta-cell identity transcription factors and beta-cell dysfunction. In silico analyses using dynamic optimal transport (TrajectoryNet) demonstrate that CCK-expressing beta-cells arise from pre-existing insulin low-expressing beta-cells, arguing for baseline beta-cell heterogeneity as a determinant of aberrant hormone expression. Lastly, transgenic expression of CCK or Iapp in beta-cells was sufficient to promote oncogenic Kras-driven pancreatic tumorigenesis, while converse beta-cell ablation impeded tumor progression in mice. Together, these results uncover a novel mechanism of obesity driven PDAC by local hormonal signaling between endocrine islets and exocrine acinar cells and reveal pancreatic endocrine adaptations that could be targeted to halt exocrine tumorigenesis. Citation Format: Cathy C. Garcia, Lauren Lawres, Sherry Agabiti, Jaffarguriqbal Singh, Alex Tong, Aarthi Venkat, Daniel B. Burkhardt, Rebecca Cardone, Richard G. Kibbey, Smita Krishnaswamy, Mandar D. Muzumdar. Elucidating mechanisms of endocrine-exocrine signaling in obesity-driven pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C050.

This is a case of Aspergillus infection in a twenty year old male presenting as an insidiously growing intradural spinal cord tumour with signs of cord compression. There was no definite portal of entry and the patient had no signs of immunsuppression. It is believed that such a case has not been previously reported. The lesion resembled a benign tumour on preoperative imaging and intraoperative consistency and vascularity. The lesion was successfully and completely resected. MR images of this unusual lesion are presented.

Arachnoid cysts are rare lesions occurring anywhere in the cerebrospinal axis. The sylvian fissure remains the most favoured site for their occurrence, followed by cerebellopontine angle, suprasellar, and quadrigeminal cisterns. Retroclival arachnoid cysts are very rare. We report a retroclival arachnoid cyst with bilateral cerebellopontine angle extensions with hemifacial spasm in a 26-year-old woman. The patient underwent surgery and her hemifacial spasm improved.

Extracranial spread of recurrent meningiomas involving the middle ear is rare. We present the case of a 59-year-old woman with headache and swelling of scalp over the right temporal region. MRI revealed a lesion in the right temporal lobe suggestive of meningioma. She underwent complete surgical excision of the lesion followed by post-operative radiotherapy. After 1 year, she presented with right-sided otalgia and a middle-ear mass extruding into the external auditory canal. She was re-operated and histopathology was anaplastic meningioma. We are discussing this unusual pattern of recurrence in our patient with a review of literature.

The most common secondary neoplasms which occur following cranial radiation therapy are sarcoma and meningioma. The occurrence of glioblastoma multiforme following radiation and chemotherapy in acute lymphocytic leukaemia (ALL) is rare. We report 3 cases of glioblastoma multiforme in children developing 11-72 months following completion of chemotherapy/radiotherapy for ALL. The exact cause for the development of glioblastoma multiforme following therapy for ALL is not clear. A genetic predisposition may be essential for the occurrence of such a highly malignant primary brain tumour in leukaemia patients, irrespective of radiation and/or chemotherapy. The pathogenesis and surgical management are discussed, and the literature on the subject is reviewed.

Three rare cases of stenosis of spinal canal at the level of atlas associated with atlantoaxial dislocation are presented. An atlantoaxial lateral mass fixation with plate and screws after posterior midline bony decompression was successfully performed in these cases.

An unusual astrocytoma occurring in different anatomical compartments of the brain is reported. The child was operated upon for a cerebellar astrocytoma when he was eight-and-half years old. Seven years later, he was operated for a cerebral astrocytoma. The growth of the similar tumours at these two sites is analysed and literature on the subject is reviewed. The concept of multicentricity is emphasized.

Lateral cutaneous femoral nerve (LCFN) injury or Meralgia paraesthetica (MP) results in restriction of activity. Compression of the nerve by disc hernia, retroperitoneal tumors, and external pressure around the anterior superior iliac spine is common. However, it is not commonly observed after lumbar spinal surgery in prone position.In this prospective study of 110 patients who underwent elective lumbar spinal surgery, managed from January 2002 to June 2002, the incidence, possible risk factors, etiopathogenesis and management of MP were analyzed.There were 66 males and 44 females. The age of the patients ranged from 15 to 81 years (mean 46.9 yrs.). Thirteen patients (12%) suffered from MP. It is more common in thinner individuals due to pressure injury to the nerve at its exit point. Ninety-two per cent of the patients were asymptomatic at follow-up after 6 months. In 7 out of 13 patients, patchy sensory loss on clinical examination was seen at 6 months.MP after posterior lumbar spinal surgery is uncommon. Smaller bolsters may avoid some of the vulnerable pressure points, as the surface area available is relatively smaller. The posts of the Hall-Relton frame over the anterior superior iliac crest should be adequately padded. The condition is usually self-limiting. Surgical division or decompression of the LCFN is reserved for persistent or severe MP.

We report a series of three patients with suprasellar arachnoid cysts who presented with a rare 'bobble-head doll' syndrome. The abnormal head movements improved after surgical evacuation of the cysts in all the three cases. Various pathophysiological mechanisms involved in the bobble-head doll syndrome are discussed. The literature on suprasellar arachnoid cysts is briefly reviewed.

An 8-year-old boy with no evidence of von Recklinghausen's disease presented with an unusual neurinoma manifesting as a gradually progressive swelling in the suboccipital region over 2 years. The lesion was massive and had widely eroded the posterior aspects of the atlas, axis, and suboccipital bone. The tumor had involved the dura of the sigmoid and transverse sinuses, was highly vascular, and had encased the ipsilateral vertebral artery. The tumor was almost completely resected although with considerable loss of blood through a large rent in the right sigmoid sinus. This unusual benign neurinoma most probably arose from the second cervical ganglion.

A 35-year-old male presented with symptoms of 'pathological laughter' occurring for 6 months and progressive ataxia and right facial nerve paresis for 2 months. Neuroimaging revealed a large petroclival meningioma. The tumor was well defined and only moderately vascular, and could be relatively easily resected. The symptom of pathological laughter disappeared immediately and his gait improved to normal within a week of surgery. Pathological laughter as a presenting symptom of petroclival meningioma is extremely rare. The symptom of pathological laughter may have localizing value.

Sinus pericranii is a rare vascular anomaly. A case of sinus pericranii at the nasion with an orbital extension is presented. The drainage was into the superior sagittal sinus. The pathogenesis is discussed and the literature is reviewed.

A 26-year-old, short statured, obese male presented with a mature teratoma located entirely within the dural confines of the sella manifesting as headaches and progressive loss of vision. He had panhypopituitarism. Magnetic resonance imaging showed a large sellar-suprasellar but entirely infradiaphragmatic tumor of varying consistency. The tumor was resected through a trans-sphenoidal route. The tumor had elevated the diaphragma sellae to a significant extent but did not pass through. Histological examination confirmed a mature teratoma.

A 20-day-old female neonate presented with an immature teratoma in the midline posterior fossa. The tumor was totally removed but the patient died of pneumonia. Teratoma is a rare tumor, but very difficult to treat as the patients tend to be young, and the outcome is very poor.

A rare case of an epidermoid tumor lying within Meckel's cave is reported. A 27-year-old housewife presented with complaints of right facial hypesthesia for two and a half years. On examination she had partial loss of touch sensation in the right trigeminal nerve distribution. Magnetic resonance imaging revealed a tumor located at the right petrous apex and cavernous sinus. The epidermoid tumor was excised through a lateral basal subtemporal approach. The symptoms resolved following surgery.

An unusual complication following a craniotomy is reported. The free bone flap migrated over the adjacent bone four weeks following surgery and needed operative readjustment. The probable causes for such a complication are analysed and discussed.

The impact of efforts by the Medical College Hospital and the Regional Family Planning Training Centre in Aurangabad, India, to popularize family planning in the city's slum areas was assessed through a KAP survey conducted by medical interns, social workers, and other hospital staff. In all, 237 couples were surveyed. Of these, 156 were Nav Buddhas, 53 were Hindus, 17 were Christians and 11 were Muslims. When asked if they were aware of birth control, 108 replied in the affirmative (the "Aware" group) and 129 were ignorant (the "Unaware" group). Only 21 from the "Aware" group were practicing a family planning method. Of the 21 acceptors, there were 15 vasectomies, 3 tubectomies, and in 3 cases, use of the condom by the husband. The most common reason for failure to practice contraception was the desire for more children, although many felt that contraception was unnecessary or they had neglected to think about family limitation. It is important that only 33 out of 237 (14%) recognized the widely publicized symbol for family planning (inverted red triangle); and the proportion of contraception acceptors in this group was significantly more than among those who failed to recognize the symbol. Survey findings indicated that efforts to reach the population in the ever-increasing slums in urban areas must be intensified.