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Therapeutic options for managing Pancreatic ductal adenocarcinoma (PDAC), one of the deadliest types of aggressive malignancies, are limited and disappointing. Therefore, despite suboptimal clinical effects, gemcitabine (GEM) remains the first-line chemotherapeutic drug in the clinic for PDAC treatment. The therapeutic limitations of GEM are primarily due to poor bioavailability and the development of chemoresistance resulting from the addiction of mutant-K-RAS/AKT/ERK signaling-mediated desmoplastic barriers with a hypoxic microenvironment. Several new therapeutic approaches, including nanoparticle-assisted drug delivery, are being investigated by us and others. This study used pH-responsive nanoparticles encapsulated ERK inhibitor (SCH772984) and surface functionalized with tumor-penetrating peptide, iRGD, to target PDAC tumors. We used a small molecule, SCH772984, to target ERK1 and ERK2 in PDAC and other cancer cells. This nanocarrier efficiently released ERKi in hypoxic and low-pH environments. We also found that the free-GEM, which is functionally weak when combined with nanoencapsulated ERKi, led to significant synergistic treatment outcomes in vitro and in vivo. In particular, the combination approaches significantly enhanced the GEM effect in PDAC growth inhibition and prolonged survival of the animals in a genetically engineered KPC (LSL-KrasG12D/+/LSL-Trp53R172H/+/Pdx-1-Cre) pancreatic cancer mouse model, which is not observed in a single therapy. Mechanistically, we anticipate that the GEM efficacy was increased as ERKi blocks desmoplasia by impairing the production of desmoplastic regulatory factors in PDAC cells and KPC mouse tumors. Therefore, 2nd generation ERKi (SCH 772984)-iRGD-pHNPs are vital for the cellular response to GEM and denote a promising therapeutic target in PDAC with mutant K-RAS., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

The aberrant glycosylation is a hallmark of cancer progression and chemoresistance. It is also an immune therapeutic target for various cancers. Tunicamycin (TM) is one of the potent nucleoside antibiotics and an inhibitor of aberrant glycosylation in various cancer cells, including breast cancer, gastric cancer, and pancreatic cancer, parallel with the inhibition of cancer cell growth and progression of tumors. Like chemotherapies such as doxorubicin (DOX), 5'fluorouracil, etoposide, and cisplatin, TM induces the unfolded protein response (UPR) by blocking aberrant glycosylation. Consequently, stress is induced in the endoplasmic reticulum (ER) that promotes apoptosis. TM can thus be considered a potent antitumor drug in various cancers and may promote chemosensitivity. However, its lack of cell-type-specific cytotoxicity impedes its anticancer efficacy. In this review, we focus on recent advances in our understanding of the benefits and pitfalls of TM therapies in various cancers, including breast, colon, and pancreatic cancers, and discuss the mechanisms identified by which TM functions. Finally, we discuss the potential use of nano-based drug delivery systems to overcome non-specific toxicity and enhance the therapeutic efficacy of TM as a targeted therapy.

Overactivated NLRP3 inflammasome has been shown to associate with an increasing number of disease conditions. Activation of the NLRP3 inflammasome results in caspase-1-catalyzed formation of active pro-inflammatory cytokines (IL-1β and IL-18) resulting in pyroptosis. The multi-protein composition of the NLRP3 inflammasome and its sensitivity to several damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) make this extensively studied inflammasome an attractive target to treat chronic conditions. However, none of the known NLRP3 inhibitors has been approved for clinical use. Sulfonylurea and covalent inhibitors with electrophilic warhead (Michael acceptor) are among the prominent classes of compounds explored for their NLRP3 inhibitory effects. Chalcone, a small molecule with α, β unsaturated carbonyl group (Michael acceptor), has also been studied as a promising scaffold for the development of NLRP3 inhibitors. Low molecular weight, easy to manipulate lipophilicity and cost-effectiveness have attracted many to use chalcone scaffold for drug development. In this review, we highlight chalcone derivatives with NLRP3 inflammasome inhibitory activities. Recent developments and potential new directions summarized here will, hopefully, serve as valuable perspectives for investigators including medicinal chemists and drug discovery researchers to utilize chalcone as a scaffold for developing novel NLRP3 inflammasome inhibitors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Donepezil (DNPZ) is one of the few FDA-approved widely used medication in the clinical care of Alzheimer's disease (AD) patients. To investigate the effect of geometry and to find the significance of an enol form if any in DNPZ on acetylcholinesterase (AChE) inhibition, we changed the tetrahedral geometry of DNPZ to planar trigonal pyramidal geometry by replacing the α-carbon atom next to ketone functionality with a nitrogen atom. To mimic 1-indanone in DNPZ, we selected 1-isoindolinone framework to synthesize 25 new DNPZ derivatives and characterized using 1 H NMR, 13 C NMR and ESI-MS spectroscopy methods. Drug likeliness profile for each compound was predicted using Molinspiration online software following Lipinski's rule. Commercially available assay kits were used to measure AChE and butyrylcholinesterase (BuChE) inhibitory effects. NIH/3T3 mouse embryonic fibroblast cell line was used to measure cytotoxic and proliferation effects using LDH and MTT assay, respectively. Compound #20 was selected for comparative computational docking, modelling and physicochemical studies. Our results show that DNPZ with tetrahedral geometry has 3-fold higher AChE inhibition as compared to compound #20 with planar trigonal pyramidal geometry. Our approach may be useful as a novel indirect method to study the significance of the enol form in DNPZ (or similar compounds), since constant interconversion between the keto and enol forms does not permit a direct determination of the effect of the enol form of DNPZ in vivo . Overall, we conclude that the tetrahedral is a better fit and any change in geometry significantly drives down the cholinesterase inhibitory effect of DNPZ., Competing Interests: Conflicts of Interest The authors declare no conflicts of interest

Chalcone [(E)-1,3-diphenyl-2-propene-1-one], a small molecule with α, β unsaturated carbonyl group is a precursor or component of many natural flavonoids and isoflavonoids. It is one of the privileged structures in medicinal chemistry. It possesses a wide range of biological activities encouraging many medicinal chemists to study this scaffold for its usefulness to oncology, infectious diseases, virology and neurodegenerative diseases including Alzheimer's disease (AD). Small molecular size, convenient and cost-effective synthesis, and flexibility for modifications to modulate lipophilicity suitable for blood brain barrier (BBB) permeability make chalcones a preferred candidate for their therapeutic and diagnostic potential in AD. This review summarizes and highlights the importance of chalcone and its analogs as single target small therapeutic agents, multi-target directed ligands (MTDLs) as well as molecular imaging agents for AD. The information summarized here will guide many medicinal chemist and researchers involved in drug discovery to consider chalcone as a potential scaffold for the development of anti-AD agents including theranostics., (Published by Elsevier Inc.)

Isoindolin-1-one or 1-isoindolinone framework is referred to phthalimidines or benzo fused γ-lactams of the corresponding γ-amino carboxylic acids and has been of prime interest for scientists for last several decades. 1-Isoindolinone framework is found in a wide range of naturally occurring compounds with diverse biological activities and therapeutic potential for various chronic diseases. Recent developments in synthetic methods for their procurement have opened a new era of 1-isoindolinone chemistry. This review aims to provide an alphabetical quick reference guide to only 1-isoindolinone based natural products and its variable fused, oxidized and reduced state skeleton with information for advanced chemotaxonomic analyses, cellular targets/pathways and diverse biological activities and future use for medicinal chemistry., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Published by Elsevier B.V.)

Direct tracking of lithium ions with time and spatial resolution can provide an important diagnostic tool for understanding mechanisms in lithium ion batteries. A fluorescent indicator of lithium ions, 2-(2-hydroxyphenyl)naphthoxazole, was synthesized and used for real-time tracking of lithium ions via widefield fluorescence microscopy. The fluorophore can be excited with visible light and was shown to enable quantitative determination of the lithium ion diffusion constant in a microfluidic model system for a plasticized polymer electrolyte lithium battery. The use of widefield fluorescence microscopy for in situ tracking of lithium ions in batteries is discussed.

The action of molecular catalysts comprises multiple microscopic kinetic steps whose nature is of central importance in determining catalyst activity and selectivity. Single-molecule microscopy enables the direct examination of these steps, including elucidation of molecule-to-molecule variability. Such molecular diversity is particularly important for the behavior of molecular catalysts supported at surfaces. We present the first combined investigation of the initiation dynamics of an operational palladium cross-coupling catalyst at the bulk and single-molecule levels, including under turnover conditions. Base-initiated kinetics reveal highly heterogeneous behavior indicative of diverse catalyst population. Unexpectedly, this distribution becomes more heterogeneous at increasing base concentration. We model this behavior with a two-step saturation mechanism and identify specific microscopic steps where chemical variability must exist in order to yield observed behavior. Critically, we reveal how structural diversity at a surface translates into heterogeneity in catalyst behavior, while demonstrating how single-molecule experiments can contribute to understanding of molecular catalysts.

Isolated giant varicocele has been reported with portal hypertension that results in abnormal communication between portal venous system and testicular vein venous system resulting in retrograde backflow of blood into the testicular venous system which leads to varicosity of the pampiniform plexuses. 65-year-old male with no past medical or surgical history presented to us with soft inguinoscrotal swelling that disappears on lying down mimicking inguinal hernia. Clinical examination revealed soft inguionoscrotal swelling that disappears on pressure. Ultrasonography revealed varicosity of pampiniform plexus, and CT angiography to trace the extent of the varicosity revealed abnormal communication of right testicular vein with superior mesenteric vein. There was no evidence of any portal hypertension; the cause of the portosystemic shunt remains obscure, and it might be a salvage pathway for increasing portal pressure. The case is noteworthy for its rare presentation and abnormal communication with portal venous system in the absence of evidence of portal hypertension.

Recurrent upper urinary tract (renal) infections have been reported to be frequent in patients with autosomal dominant polycystic kidney disease and often difficult to treat. Female preference and enteric organism predominance suggest that these renal infections are acquired to retrograde from the lower urinary tract. We encountered a rare case of bilateral polycystic kidneys with spontaneous intraperitoneal rupture of multiple infected renal cysts causing generalized peritonitis leading to severe sepsis with multiorgan failure. The patient is successfully managed with nephrectomy followed by prolonged supportive care in intensive care unit.

Cancer pain remains undertreated and a significant number of patients with cancer pain die from severe untreated pain. With increasing survival rate in cancer, the prevalence of cancer pain is also increasing in number. Though majority of patients with cancer pain can be effectively treated with conventional medical management, still a significant portion of patients required some form of interventional pain management techniques. Among the interventional techniques, intrathecal drug delivery is increasingly used in cancer pain management. Our objective of this article is to review literatures and clinical studies on intrathecal drug delivery system (IDDS) in cancer pain management and to provide updates on its use, precautions, contraindications, side effects and its management, socioeconomic consideration, and management of IDDS in difficult or uncommon situations.

The complexity of pain and pain care is such that there may come a point in the treatment of a patient with pain when a simple approach to management is no longer possible. The proverbial analgesic ladder can be rapidly overtaken when attempting palliative management of long-term or severe end-of-life pain. Epidural steroid injection is frequently used procedure in chronic back pain of neuropathic origin in nonmalignant cases. This case report implicates the use of epidural steroid for the management of severe neuropathic symptoms including allodynia and hyperalgesia in the setting of cancer pain and palliative care.

Objective: Cases of chronic noncancer pain are both the most frequent and the most difficult that the spine care professional is called upon to treat. We use this case to illustrate the potential effectiveness of repeat positional upright, weight-bearing magnetic resonance (MR) imaging to diagnose disorders and to detect changes in disorders., Clinical Features: We present the case of a 35-year-old man referred to our neurosurgical clinic with complaints of chronic, noncancer lower back pain and right-greater-than-left sciatica. Traditional recumbent MR imaging had revealed degenerative disk disease at L5-S1 and a 2.2-mm (grade 1) degenerative spondylolisthesis. The patient had not improved after more than a year of conservative treatments and, moreover, had been prescribed opiates for pain management that were potentially masking changes in his condition., Intervention and Outcomes: After referral to our clinic, we ordered repeat lumbar MR imaging in an upright weight-bearing position (sitting) 14 months after the patient's recumbent MR imaging. The weight-bearing MR imaging revealed a 9.13-mm (grade 1) degenerative spondylolisthesis at L5-S1. The patient underwent arthrodesis. His leg pain and back were significantly and clinically improved., Conclusion: When patients with noncancer, lower back pain worsen, fail to improve, or require opiates to manage their pain, updated clinical diagnosis including repeat positional imaging may be an effective diagnostic strategy.

Background: Magnetic resonance imaging has the diagnostic advantages of being noninvasive and able to visualize soft tissue. However, conventional recumbent MRI may underestimate a disease because the position of imaging takes stress off the spine., Case Description: A 37-year-old woman presented with complaints of pain in the neck that radiated down her right arm when she turned her head to the right and increased with extension. She complained of paresthesias, numbness/tingling in the index and middle fingers and thumb, in the C6 and C7 nerve root dermatomes. Conventional conservative measures, including anti-inflammatories, muscle relaxants, opiates, and physical therapy, had been tried without positive results. Magnetic resonance imaging was performed in a weight-bearing upright neutral position, in the extended upright position, and in the extended upright position with the head turned to the right. The latter images showed a clear protrusion at C5-C6 and C6-C7. These protrusions were not clearly evident in the upright neutral position. A targeted epidural block at C5-C6 and C6-C7 relieved the patient's pain, and she has been able to continue work., Conclusions: Magnetic resonance imaging of the cervical spine in the position that causes the patient's symptoms may increase the sensitivity and accuracy of the diagnostic study and thus provide the spine-care professional with a potentially more accurate diagnosis and a targeted treatment plan. Such MRIs may also decrease the need for myelography.

A furo-fused BINOL based chiral crown was developed as an enantioselective chiral sensor for phenylethylamine and ethyl ester of valine. Fusion of furan to BINOL has resulted in a highly stereo-discriminating backbone for the chiral crown developed. This chiral crown exhibited a fluorescence enhancement difference of 2.97 times between two enantiomers of phenylethylamine and 2.55 times between two enantiomers of ethyl ester of valine. The ratio of association constants for two diastereomeric complexes of two enantiomers of phenylethylamine was found to be 11.30, and the ratio for two enantiomers of ethyl ester of valine was 7.02.