A Lipophilic Salt Form to Enhance the Lipid Solubility and Certain Biopharmaceutical Properties of Lapatinib.

Lapatinib (LTP) commercially available as lapatinib ditosylate (LTP-DTS) salt is the only drug approved for the treatment of HER-positive metastatic breast cancer. A low and pH-dependent solubility results in poor and variable oral bioavailability, thus driving significant interest in molecular modification and formulation strategies of the drug. Furthermore, due to very high crystallinity, LTP and LTP-DTS have low solubility in lipid excipients, making it difficult to be delivered by lipid-based carrier systems. Thus, the present work reports a new salt form of LTP with a docusate counterion to enhance the pharmaceutical properties of the drug (LTP-DOC). NMR spectra showed a downfield shift of the methylene singlet proton from 3.83 and 4.41 ppm, indicating a lowering of electron density on the adjacent nitrogen atom and confirming the formation of amine-sulfonyl salt through the specified basic nitrogen center located adjacent to the furan ring. PXRD diffractograms of LTP-DOC indicated a reduced crystallinity of the prepared salt. The dissolution, equilibrium solubility, lipid excipient solubility, partitioning coefficient, distribution coefficient, tabletability, and in vitro cytotoxicity of the lipophilic salt of LTP were investigated. The equilibrium solubility data showed that LTP-DOC possesses a pH-independent solubility profile in the pH range of 3.5 to 7.4 with a 3.14 times higher permeability coefficient than commercial ditosylate salt. Furthermore, the prepared LTP-DOC salts showed twice higher log P than the free base and 8 times higher than LTP-DTS. The prepared LTP-DOC was found to have 4- to 9-fold higher solubility in lipid excipients like Capmul MCM C8 and Maisine CC compared to the ditosylate salt. The LTP-DOC salt was tabletable and showed approximately 1.2 times lower dissolution than commercial ditosylate salt, indicating extended-release behavior. A cytotoxicity study of LTP-DOC salt showed an approximately 2.5 times lower IC50 value than the LTP-free base and 1.7 times lower than commercial ditosylate salt with an approximately 3 times higher selectivity index. The investigations strongly indicate a high translational potential of the prepared salt form in maintaining solubility-lipophilicity interplay, enhancing the drug's bioavailability, and developing lipidic formulations.

Serum miR-215-5p, miR-192-5p and miR-378a-5p as novel diagnostic biomarkers for periampullary adenocarcinoma.

OBJECTIVE: MicroRNAs (miRNAs) are present in human serum in a stable form. Circulating miRNAs are increasingly recognized as promising biomarkers for early cancer detection. The aim of this study was to identify serum miRNAs as biomarkers for periampullary adenocarcinoma (PAC). PATIENTS AND METHODS: 68 patients with PAC and 50 healthy controls (HCs) subjects were recruited in this study. The expression levels of 11 selected miRNAs were determined in serum samples using the SYBR-green quantitative reverse transcription polymerase chain reaction (qRT-PCR) method. Receiver operating characteristic (ROC) analysis was used to evaluate the diagnostic potential of serum miRNAs. RESULTS: The expression levels of three miRNAs (miR-215-5p, miR-192-5p, and miR-378a-5p) were significantly upregulated in the serum samples derived from the PAC patients compared with those from the HC (p < 0.001). The ROC analysis showed that all three significantly altered miRNAs (miR-215-5p, miR-192-5p, and miR-378a-5p) could potentially discriminate patients with PAC from HC with AUC value of 0.771 (95% CI: 0.684-0.843), 0.877 (95% CI: 0.799-0.927) and 0.768 (95% CI: 0.674-0.853) respectively. Further comparisons showed that these three serum miRNAs (miR-215-5p, miR-192-5p, and miR-378a-5p) can strongly discriminate early-stage PAC patients from HC with an AUC value of 0.802 (95% CI: 0.719-0.886), 0.870 (95% CI: 0.793-0.974) and 0.793 (95% CI: 0.706-0.880) respectively, may aid in early detection of PAC. CONCLUSIONS: Taken together, our findings demonstrated that these three serum miRNAs (miR-215-5p, miR-192-5p, and miR-378a-5p) may serve as noninvasive biomarkers for the early detection of PAC.

Ellagic Acid Reverses Alterations in the Expression of AMPA Receptor and Its Scaffolding Proteins in the Cerebral Cortex and Memory Decline in STZ-sporadic Alzheimer' s Disease Mouse Model.

RATIONALE: Alzheimer's disease (AD), an age-dependent devastating neuropsychiatric disorder, is a leading cause of learning, memory and intellectual disabilities. Current therapeutic approaches for the amelioration of the anomalies of AD are not effective. OBJECTIVE: In the present study, the molecular mechanisms underlying sporadic AD (sAD), the memory related behavioral analysis and neuroprotective effects of Ellagic acid (EA) were investigated. METHOD: sAD mouse model was developed by intracerebroventricular (ICV) injection of Streptozotocin (STZ). The efficacy of EA, a naturally occurring polyphenol, in amelioration of anomalies associated with sAD was assessed. EA was administered once daily for 28 days at a dose of 75 mg/kg body weight followed by neurobehavioral, biochemical, molecular and neuronal count analysis to delineate the mode of action of EA. RESULT: The ICV injection of STZ in mice significantly increased the expression of AD biomarkers in addition to enhanced oxidative stress. A decline in the discrimination index in Novel Object Recognition Test was observed indicating the compromise of recognition memory in AD. Studies on the expression of genes involved in synaptic plasticity reveal the dysregulation of the α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) of the glutamate and its scaffolding proteins in the postsynaptic density and thereby synaptic plasticity in AD. ICV-STZ led to significant upregulation of apoptotic markers which led to decrease in neuronal density of the cerebral cortex. EA significantly reversed the above and improved anomalies of sAD. CONCLUSION: EA was observed to profoundly modulate the genes involved in AD pathophysiology, restored antioxidant enzymes activity, reduced lipid peroxidation and neuronal loss in the sAD brain. Further, EA was observed to effectively modulate the genes involved in apoptosis and synaptic plasticity. Therefore, EA possesses promising anti-AD properties, which may improve AD-associated anomalies by modulating synaptic plasticity via AMPAR signaling.

Clinical Significance of MUC4 and Associated Proteins in Pancreatic and Periampullary Cancers.

OBJECTIVE: This study primarily aimed to assess the expression of MUC4 in patients with pancreatic ductal adenocarcinoma (PDAC) as compared with controls and assess its clinical relevance. MATERIALS AND METHODS: Serum MUC4 levels and MUC4 gene expression in snap-frozen tissue were analyzed through surface plasmon resonance and quantitative polymerase chain reaction, respectively. Tumor tissues and control tissues were analyzed for MUC4 and other mucins through immunohistochemistry. RESULT: MUC4 expression in tumor tissue was found to be significantly elevated in PDAC patients as compared with chronic pancreatitis tissues and normal pancreatic tissues. Periampullary carcinoma and cholangiocarcinoma tissue also showed increased expression of MUC4 and other mucins. CONCLUSIONS: Differential expression of MUC4 in pancreatic tumor tissues can help to differentiate PDAC from benign conditions.

Natural food flavours: a healthier alternative for bakery industry-a review.

Human beings always remained attracted towards vivid food flavours and aroma. Ever since the food industry came into existence, several brands and industries worldwide have been busy creating storms in the food markets through flavours, aromas, textures and substances to intrigue the consumers' minds. The ingredients that go into the preparation of these food items include a list of various preservatives, taste enhancers, stabilizers, colours and to make it look attractive and delicious but may not be healthy. Most of the flavours that are used by food brands are often chemical based and are synthesized completely in the laboratory. The use of artificial/synthetic flavourings in the form of chemical food additives and taste enhancers lead to long term health issues which include potential risks of neurological problems, cytotoxicity, genotoxicity, different types of hypersensitivities and even cancers. Food and Drug Administration (FDA, USA) conduct frequent studies to limit the use of artificial flavouring and additives which are totally chemical based and mimic natural food flavours and extract. Benzaldehyde-an organic chemical closely resembles the flavour of roasted almonds and ethyl vanillin which is 3 times potent than natural vanilla extract used is various confectionery items. Also several ester derivatives are used for mimicking natural fruit flavours like strawberry, guava and cherry. These chemicals pose a considerable threat to human health, knowingly or unknowingly. Antagonistically, natural food flavours, though not as popular as artificial ones prove to be healthier and carry the same aroma and taste as artificial flavouring agents. This review paper sheds light on the pervasiveness of natural and artificial food flavouring agents in the market, their benefits and drawbacks and how they have been in a constant race for dominating the bakery industry.

MicroRNA Signatures for Pancreatic Cancer and Chronic Pancreatitis: Expression Profiling by NGS.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease due to the lack of early detection. Because chronic pancreatitis (CP) patients are a high-risk group for pancreatic cancer, this study aimed to assess the differential miRNA profile in pancreatic tissue of patients with CP and pancreatic cancer. METHODS: MiRNAs were isolated from formalin-fixed paraffin-embedded pancreatic tissue of 22 PDAC patients, 18 CP patients, and 10 normal pancreatic tissues from autopsy (C) cases and processed for next-generation sequencing. Known and novel miRNAs were identified and analyzed for differential miRNA expression, target prediction, and pathway enrichment between groups. RESULTS: Among the miRNAs identified, 166 known and 17 novel miRNAs were found exclusively in PDAC tissues, while 106 known and 10 novel miRNAs were found specifically in CP tissues. The pathways targeted by PDAC-specific miRNAs and differentially expressed miRNAs between PDAC versus CP tissues and PDAC versus control tissues were the proteoglycans pathway, Hippo signaling pathway, adherens junction, and transforming growth factor-ß signaling pathway. CONCLUSIONS: This study resulted in a set of exclusive and differentially expressed miRNAs in PDAC and CP can be assessed for their diagnostic value. In addition, studying the role of miRNA-target gene interactions in carcinogenesis may open new therapeutic avenues.

Adaptation of a Clinical High-Frequency Transrectal Ultrasound System for Prostate Photoacoustic Imaging: Implementation and Pre-clinical Demonstration.

OBJECTIVE: High-frequency, high-resolution transrectal micro-ultrasound (micro-US: ≥15 MHz) imaging of the prostate is emerging as a beneficial tool for scoring disease risk and accurately targeting biopsies. Adding photoacoustic (PA) imaging to visualize abnormal vascularization and accumulation of contrast agents in tumors has potential for guiding focal therapies. In this work, we describe a new imaging platform that combines a transrectal micro-US system with transurethral light delivery for PA imaging. METHODS: A clinical transrectal micro-US system was adapted to acquire PA images synchronous to a tunable laser pulse. A transurethral side-firing optical fiber was developed for light delivery. A polyvinyl chloride (PVC)-plastisol phantom was developed and characterized to image PA contrast agents in wall-less channels. After resolution measurement in water, PA imaging was demonstrated in phantom channels with dyes and biodegradable nanoparticle contrast agents called porphysomes. In vivo imaging of a tumor model was performed, with porphysomes administered intravenously. RESULTS: Photoacoustic imaging data were acquired at 5 Hz, and image reconstruction was performed offline. PA image resolution at a 14-mm depth was 74 and 261 µm in the axial and lateral directions, respectively. The speed of sound in PVC-plastisol was 1383 m/s, and the attenuation was 4 dB/mm at 20 MHz. PA signal from porphysomes was spectrally unmixed from blood signals in the tumor, and a signal increase was observed 3 h after porphysome injection. CONCLUSION: A combined transrectal micro-US and PA imaging system was developed and characterized, and in vivo imaging demonstrated. High-resolution PA imaging may provide valuable additional information for diagnostic and therapeutic applications in the prostate.

Elevated levels of peripheral Th17 cells and Th17-related cytokines in patients with periampullary adenocarcinoma.

AIM: Periampullary adenocarcinoma (PAC) is a malignant tumor originating at the ampulla of Vater, distal common bile duct, head of the pancreas, ampulla and duodenum. The levels of circulating Th17 cells and Th17-related cytokines in patients with PAC remain unreported. Therefore, the aim of this study was to determine the levels of circulating Th17 cells and Th17-related cytokines in patients with PAC. MATERIALS AND METHODS: Flow cytometry was used to measure Th17 cell proportions in PBMCs from 60 PAC patients and 30 healthy controls. Enzyme-linked immunosorbent assay (ELISA) was used to quantify IL-17A and IL-23 levels in serum samples, while quantitative reverse transcription polymerase chain reaction (qRT-PCR) assessed IL-17A mRNA expression and Th17-related transcription factors (RORγt and STAT3) in tissue samples. RESULTS: The findings showed a substantial increase in Th17 cell percentages, elevated concentrations of IL-17A and IL-23, and higher mRNA expression levels of IL-17A, RORγt, and STAT3 in patients with PAC when compared to healthy controls (HCs). CONCLUSION: Th17 cells play an important role in the pathogenesis of PAC and may represent potential therapeutic targets.

Supramolecular Nanostructures for the Delivery of Peptides in Cancer Therapy.

Supramolecular nanostructured based delivery systems are emerging as a meaningful approach in the treatment of cancer, offering controlled drug release and improved therapeutic efficacy. The self-assembled structures can be small molecules, polymers, peptides, or proteins, which can be used and functionalized to achieve tailored release and target specific cells, tissues, or organs. These structures can improve the solubility and stability of drugs having low aqueous solubility by encapsulating and protecting them from degradation. Alongside, peptides as natural biomolecules have gained increasing attention as potential candidates in cancer treatment because of their biocompatibility, low cytotoxicity, and high specificity toward tumor cells. The amino acid sequences in peptide molecules are tunable, efficiently controlling the morphology of peptide-based self-assembled nanosystems and offering flexibility to form supramolecular nanostructures (SNs). It is evident from the current literature that the supramolecular nanostructures based delivery of peptide for cancer treatment hold great promise for future cancer therapy, offering potential strategies for personalized medicine with improved patient outcomes. SIGNIFICANCE STATEMENT: This review focuses on fundamentals and various drug delivery mechanisms based on SNs. Different SN approaches and recent literature reviews on peptide delivery are also presented to the readers.

Elucidating the Role of miRNA-326 Modulating Hedgehog Signaling in Pancreatic Carcinoma.

BACKGROUND AND AIM: Pancreatic ductal adenocarcinoma (PDAC) is one of the lethal malignancies worldwide characterized by poor prognosis. MicroRNAs (miRNAs) function as the key regulators in carcinogenesis and may act as noninvasive biomarkers in various malignancies including PDAC. The present study aimed to elucidate the role of miR-326, a known modulator of hedgehog (Hh) pathway in PDAC. MATERIALS AND METHODS: miR-326 circulating levels were assessed in 105 PDAC patients, 31 with chronic pancreatitis (CP) and 36 healthy controls by quantitative Polymerase chain reaction. The expression of miR-326 and smoothened (SMO) was checked in surgical PDAC tissue. SMO protein expression was analyzed by immunohistochemistry in different groups. Finally, the role of miR-326 as a modulator of Hh pathway was assessed in vitro. RESULTS: Our results demonstrate that miR-326 is downregulated in both blood and tissue of PDAC patients as compared with controls. In contrast, the target gene/protein expression of SMO is upregulated in PDAC. Moreover, the tumor stromal expression of SMO was found to be clinically associated with lymph-node metastasis and vascular encasement in PDAC. Overexpression of miR-326 in Panc1 cell line was found to induce downregulation of SMO suggesting the tumor suppressor role of miR-326 in PDAC. CONCLUSIONS: Taken together, miR-326 acts as a tumor suppressor in PDAC by modulating Hh pathway. It may be a promising target for the development of efficient drug therapies for the treatment of PDAC.

Comparison of the immunogenicity and safety of Euvichol-Plus with Shanchol in healthy Indian adults and children: an open-label, randomised, multicentre, non-inferiority, parallel-group, phase 3 trial.

Background: Considering the cholera menace in India and to seek licensure of the oral cholera vaccine (OCV), Euvichol-Plus, we conducted a clinical trial to compare the immunogenicity and safety of Euvichol-Plus with Shanchol in healthy Indian adults and children. Methods: This phase 3, open-label, multicentre, randomised, non-inferiority, parallel-group, comparative study was conducted at seven sites across India involving 416 healthy adults (aged ≥18-60 years) and children (aged ≥1 to <18 years). Healthy individuals who agreed to participate through a voluntary written informed consent form along with oral or written assent (for children aged 7-18 years) were included. No assent was required for those <7 years, as consent was given by the legally acceptable representatives (LAR). Participants were randomised 1:1 to receive two doses of either Euvichol-Plus or Shanchol orally, 14 days apart. The first dose (1.5 ml) was administered on visit 1, and the second dose at 2 weeks after the first dose during visit 2. Participants were followed up telephonically for 3 consecutive days after each visit and returned for final assessment at 2 weeks after the second dose (visit 3). Blood samples were collected for immunogenicity assessment, and safety analyses were done during all the visits. The primary immunogenicity endpoint was the percentage of participants with ≥4-fold increase in anti-Vibrio cholerae (V. cholerae) O1 Ogawa and O1 Inaba (vibriocidal) antibody titres at 2 weeks after the second dose as compared to baseline titres prior to dosing. The secondary immunogenicity endpoints included the percentage of participants with ≥4-fold increase in anti-V. cholerae O139 antibody titres at 2 weeks after the second dose as compared to baseline titres, and geometric mean titres (GMT) and geometric mean ratios (GMR) as measured by anti-V. cholerae O1 Ogawa, O1 Inaba, and O139 antibody titres at 2 weeks after the second dose as compared to baseline titres. The safety endpoints included assessment of solicited, unsolicited adverse events (AEs), and serious adverse events (SAEs). The clinical trial was registered with the Clinical Trials Registry of India (CTRI/2021/08/035344). Findings: The study was performed in two age cohorts: cohort 1 (aged ≥18-60 years, 208 participants [104 in Euvichol-Plus group and 104 in Shanchol group]), and cohort 2 (aged ≥1 to <18 years, 208 participants [104 in Euvichol-Plus group and 104 in Shanchol group]). A total of 414 participants (Euvichol-Plus: 206 and Shanchol: 208) who completed the study (intention-to-treat and per-protocol set) were analysed to compare the vibriocidal titre as an index for immunogenicity. At 2 weeks after the second dose, the percentage of participants in the Euvichol-Plus group who reported a ≥4-fold increase in anti-V. cholerae antibody titres were 68.93% (O1 Ogawa) [95% CI 62.13%-75.18%], 66.02% (O1 Inaba) [95% CI 59.11%-72.46%], and 59.71% (O139) [95% CI 52.67%-66.47%] as compared to 63.94% (O1 Ogawa) [95% CI 57.01%-70.47%], 65.87% (O1 Inaba) [95% CI 58.99%-72.28%], and 56.25% (O139) [95% CI 49.22%-63.10%] in the Shanchol group. The lower limit of 95% CI for treatment difference for all the antibody titres was ≥10% (non-inferiority margin), demonstrating that Euvichol-Plus was non-inferior to Shanchol. The post-vaccination GMT (Day 14 and 28) were more than the pre-vaccination GMT for all three serotypes in both groups. The GMR obtained for Euvichol-Plus over Shanchol for O1 Ogawa, O1 Inaba, and O139 serotypes was >1, indicating non-inferiority of Euvichol-Plus to Shanchol. The safety cohort included 416 participants. Headache was the most common solicited AE, whereas cold and cough were the most common unsolicited AEs in both groups. Interpretation: Euvichol-Plus appears to be non-inferior to Shanchol in terms of immunogenicity and safety in healthy Indian adults and children. Funding: Techinvention Lifecare Private Limited, Mumbai, India.

Pulse Pressure Variance (PPV)-Guided Fluid Management in Adult Patients Undergoing Supratentorial Tumor Surgeries: A Randomized Controlled Trial.

Objective Appropriate fluid management in neurosurgery is critical due to the risk of secondary brain injury. Determination of volume status is challenging with static variables being unreliable. Goal-directed fluid therapy with dynamic variables allows reliable determination of fluid responsiveness and promises better outcomes. We aimed to compare the intraoperative fluid requirement between conventional central venous pressure (CVP)-guided and pulse pressure variance (PPV)-guided fluid management in supratentorial tumor surgeries. Materials and Methods This prospective, randomized, double-blind, single-center trial was conducted with 72 adults undergoing supratentorial tumor surgery in a supine position. Patients were divided into two groups of 36 patients each receiving CVP- and PPV-guided fluid therapy. The CVP-guided group received boluses to target CVP greater than 8 mm Hg along with hourly replacement of intraoperative losses and maintenance fluids. The PPV-guided group received boluses to target PPV less than 13% in addition to maintenance fluids. Total intraoperative fluids administered and the incidence of hypotension was recorded along with the brain relaxation score. Postoperatively, serum lactate levels, periorbital and conjunctival edema, as well as postoperative nausea and vomiting were assessed. Statistical Analyses All statistical analyses were performed with Statistical Package for Social Sciences, version-20 (SPSS-20, IBM, Chicago, Illinois, United States). To compare the means between the two groups (CVP vs. PPV), independent samples t -test was used for normal distribution data and Mann-Whitney U test for nonnormal distribution data. The chi-square test or Fischer's exact test was used for categorical variables. Results The CVP group received significantly more intraoperative fluids than the PPV group (4,340 ± 1,010 vs. 3,540 ± 740 mL, p < 0.01). Incidence of hypotension was lower in the PPV group (4 [11.1%] vs. 0 [0%], p = 0.04). Brain relaxation scores, serum lactate levels, periorbital and conjunctival edema, and incidence of postoperative nausea and vomiting were comparable between the groups. Conclusion The requirement for intraoperative fluids was less in PPV-guided fluid management with better hemodynamic stability, adequate brain conditions, and no compromise of perfusion.

Cubosomes: An Emerging and Promising Drug Delivery System for Enhancing Cancer Therapy.

Cancer and other diseases can be treated with cubosomes, which are lyotropic nonlamellar liquid crystalline nanoparticles (LCNs). These cubosomes can potentially be a highly versatile carrier with theranostic efficacy, as they can be ingested, applied topically, or injected intravenously. Recent years have seen substantial progress in the synthesis, characterization, regulation of drug release patterns, and target selectivity of loaded anticancer bioactive compounds. However, its use in clinical settings has been slow and necessitates additional proof. Recent progress and roadblocks in using cubosomes as a nanotechnological intervention against various cancers are highlighted. In the last few decades, advances in biomedical nanotechnology have allowed for the development of "smart" drug delivery devices that can adapt to external stimuli. By improving therapeutic targeting efficacy and lowering the negative effects of payloads, these well-defined nanoplatforms can potentially promote patient compliance in response to specific stimuli. Liposomes and niosomes, two other well-known vesicular systems, share a lipid basis with cubosomes. Possible applications include a novel medication delivery system for hydrophilic, lipophilic, and amphiphilic drugs. We evaluate the literature on cubosomes, emphasizing their potential use in tumor-targeted drug delivery applications and critiquing existing explanations for cubosome self-assembly, composition, and production. As cubosome dispersion has bioadhesive and compatible features, numerous drug delivery applications, including oral, ocular, and transdermal, are also discussed in this review.

Immunoinformatics-based multi-epitope containing fused polypeptide vaccine design against visceral leishmaniasis with high immunogenicity and TLR binding.

Visceral leishmaniasis (VL) is the most lethal among all leishmaniasis diseases and remains categorized as a neglected tropical disease (NTD). This study aimed to develop a peptide-based multi-epitope vaccine construct against VL using immunoinformatics methodologies. To achieve this, four distinct proteins were screened to identify peptides consisting of 9-15 amino acids with high binding affinity to toll-like receptors (TLRs), strong antigenicity, low allergenicity, and minimal toxicity. The resulting multi-epitope vaccine construct was fused in a tandem arrangement with appropriate linker peptides and exhibited superior properties related to cytotoxic T lymphocytes (CTLs), helper T lymphocytes (HTLs), and B-cell epitopes. Subsequently, a three-dimensional (3D) model of the vaccine construct was generated, refined, and validated for structural stability and immune response capabilities. Molecular docking and simulations confirmed the vaccine construct's stability and binding affinities with TLRs, with TLR4 displaying the highest binding affinity, followed by TLR2 and TLR3. Additionally, simulations predicted robust cellular and humoral antibody-mediated immune responses elicited by the designed vaccine construct. Notably, this vaccine construct includes proteins from various pathways of Leishmania donovani (LD), which have not been previously utilized in VL vaccine design. Thus, this study opens new avenues for the development of vaccines against diverse protozoan diseases.

Prostate Cancer Progression Relies on the Mitotic Kinase Citron Kinase.

Prostate cancer remains the second leading cause of cancer death in men in Western cultures. A deeper understanding of the mechanisms by which prostate cancer cells divide to support tumor growth could help devise strategies to overcome treatment resistance and improve survival. Here, we identified that the mitotic AGC family protein kinase citron kinase (CIT) is a pivotal regulator of prostate cancer growth that mediates prostate cancer cell interphase progression. Increased CIT expression correlated with prostate cancer growth induction and aggressive prostate cancer progression, and CIT was overexpressed in prostate cancer compared with benign prostate tissue. CIT overexpression was controlled by an E2F2-Skp2-p27 signaling axis and conferred resistance to androgen-targeted treatment strategies. The effects of CIT relied entirely on its kinase activity. Conversely, CIT silencing inhibited the growth of cell lines and xenografts representing different stages of prostate cancer progression and treatment resistance but did not affect benign epithelial prostate cells or nonprostatic normal cells, indicating a potential therapeutic window for CIT inhibition. CIT kinase activity was identified as druggable and was potently inhibited by the multikinase inhibitor OTS-167, which decreased the proliferation of treatment-resistant prostate cancer cells and patient-derived organoids. Isolation of the in vivo CIT substrates identified proteins involved in diverse cellular functions ranging from proliferation to alternative splicing events that are enriched in treatment-resistant prostate cancer. These findings provide insights into the regulation of aggressive prostate cancer cell behavior by CIT and identify CIT as a functionally diverse and druggable driver of prostate cancer progression. SIGNIFICANCE: The poorly characterized protein kinase citron kinase is a therapeutic target in prostate cancer that drives tumor growth by regulating diverse substrates, which control several hallmarks of aggressive prostate cancer progression. See related commentary by Mishra et al., p. 4008.

Comparison of Intraoperative Low-Dose Ketodex and Fentanyl Infusion for Postoperative Analgesia In Spine Surgery: A Prospective Randomized Double-Blind Study.

STUDY DESIGN: Prospective randomized double-blind study. PURPOSE: To assess the analgesic effects of the combination of a low-dose ketamine and dexmedetomidine (ketodex) infusion and compare it with that of fentanyl for postoperative analgesia after spine surgeries. OVERVIEW OF LITERATURE: Adequate pain management following spine surgeries is crucial. Approximately 57% of patients experience inadequate pain control in the first 24 hours following elective spine surgery, which is attributable to the extensive soft tissue and muscle damage. METHODS: The study included 60 patients graded American Society of Anesthesiologists I and II and scheduled for thoracolumbar spine surgery involving >3 vertebral levels. The patients were divided into two groups: group KD (ketodex) and group F (fentanyl). The primary objective was to compare the postoperative analgesic requirements among the groups. The secondary objectives included a comparison of the intraoperative anesthetic requirements, postoperative pain scores, hemodynamic parameters, side effects of the study drugs, and the duration of post-anesthesia care unit stay of both the groups. RESULTS: Ketodex use prolonged the mean time to first rescue analgesia (22.00±2.30 hours vs. 11.69±3.02 hours, p <0.001) and reduced the requirement of rescue analgesics in the first 24 hours postoperatively compared to fentanyl use (70.00±8.16 µg vs. 113.31±36.65 µg, p =0.03). The intraoperative requirement of desflurane was comparable between the groups (p >0.05). The postoperative pain scores were significantly lower in the group KD than in group F at most timepoints (p <0.05). Patients in group KD had a shorter post-anesthesia care unit stay than group F did (p <0.001). CONCLUSIONS: Low-dose ketodex could be a safe substitute for fentanyl infusion when employed as an anesthetic adjuvant for patients undergoing thoracolumbar spine surgeries involving >3 vertebral levels to achieve prolonged analgesia without any opioidrelated side effects.

Increased circulating Th17 cell populations in patients with pancreatic ductal adenocarcinoma.

T-helper 17 (Th17) cells are a subset of CD4+ helper T cells that produce interleukin 17 (IL-17) and play a crucial role in the pathogenesis of inflammatory and autoimmune diseases. Few studies have been conducted to determine the role of Th17 cells in the tumorigenesis and development of pancreatic ductal adenocarcinoma (PDAC); however, its role is still unclear. In this study, the percentage of circulating Th17 cells and serum levels of IL-17A and IL-23 were analyzed using flow cytometry and ELISA, respectively, in 40 PDAC patients, 30 chronic pancreatitis (CP) patients and 30 healthy controls (HC). In addition, the mRNA expression levels of IL-17A, STAT3 and RORγt in tissue samples were quantified by qRT-PCR. The results showed that the percentage of circulating Th17 cells and the concentrations of serum IL-17A and IL-23 were significantly increased in PDAC patients as compared to CP and HC (P < 0.001). In addition, the higher level of IL-17A was significantly correlated with the poor overall survival of the PDAC patients. Furthermore, the frequencies of Th17 cells and IL-17A were significantly higher in stage III+IV PDAC patients versus stage I+II. A significant increase in IL-17A, STAT3 and RORγT mRNA was observed in patients with PDAC. Taken together, these findings suggest that the increased circulating Th17 cells and serum IL-17A may be involved in the development and metastasis of PDAC, and thus represent potential targets for the treatment of PDAC.

An Analysis of Xpert Test for Diagnosing Maxillofacial Tuberculosis.

Background: Maxillofacial tuberculosis is a diagnostic challenge for surgeons. The aim of this study was to present a detailed analysis of Xpert test in diagnosing maxillofacial tuberculosis and to analyse the accuracy of Xpert test results for various tissues of maxillofacial region. Materials and Methods: In this cross-sectional study, patients were selected randomly from outpatient department. The patients who had clinical picture and differential diagnosis highly suggestive of maxillofacial tuberculosis were included. Patients were divided into three different groups depending upon the site of involvement. The samples collected from the patients were further subdivided depending upon the type of specimen. Patients were screened first by routine tests, and the negative cases were followed by Xpert test for tuberculosis. Results: A total of 54 patients were enrolled in the study, 13 patients were found to be positive for maxillofacial tuberculosis on routine screening tests for tuberculosis, and 41 tested negative on routine test and were evaluated further through Xpert test. Specimens from bone (n12), soft tissue and skin biopsy (n15) and aspirates from lymph nodes (n14) were obtained and tested. Twenty-one samples were found to be positive, and 20 were negative upon Xpert testing. There was a statistically significant difference seen between the test groups (p < 0.01) with higher frequency of negative results in routine test. The p value for various specimens containing pus, biopsies and aspirates was 0.045, 0.023 and 0.067, respectively. Conclusion: Xpert test is more accurate when compared to routine test for diagnosing maxillofacial tuberculosis. Although accuracy of Xpert test is better for pus and biopsy samples in the specimens from bone and soft tissue, it gives poor accuracy for aspirated cells. The aspirates from lymph nodes were more susceptible for false negative test.

Deregulated kinase action in prostate cancer: molecular basis and therapeutic implications.

Prostate cancer (CaP) remains the second leading cause of cancer-related mortality in American men. Systemic treatments for metastatic CaP, which causes the majority of deaths, include androgen deprivation therapy and chemotherapy. These treatments induce remissions but do not cure CaP. Novel and functionally diverse therapeutic targets that control the cell biology that drives aggressive CaP progression are needed to overcome treatment resistance. Because signal transduction that mediates CaP cell behavior is tightly regulated by phosphorylation, kinases have attracted interest as alternative targets for CaP treatments. Here, we examine emerging evidence from recent NextGen sequencing and (phospho) proteomics analyses on clinical CaP specimens that were obtained during lethal disease progression to determine the role of deregulated kinase action in CaP growth, treatment resistance, and recurrence. We provide an overview of kinases that are impacted by gene amplification, gene deletion or somatic mutations during the progression from localized treatment-naïve CaP to metastatic castration-resistant CaP or neuroendocrine CaP, and the potential impact of such alterations on aggressive CaP behavior and treatment efficacy. Furthermore, we review knowledge on alterations in the phosphoproteome that occur during the progression to treatment-resistant CaP, the molecular mechanisms in the control of these changes, and the signal transduction associated with them. Finally, we discuss kinase inhibitors under evaluation in CaP clinical trials and the potential, challenges, and limitations to moving knowledge on the CaP kinome forward to new therapeutic strategies.

Prevention of pain on injection of propofol using ice gel pack versus pre-treatment with lignocaine: a randomized controlled trial.

PURPOSE: Regardless of the positive attributes of propofol, it is frequently associated with pain on injection. We compared the efficacy of topical cold thermotherapy using an ice gel pack with intravenous lignocaine pre-treatment for reducing pain on propofol injection. METHODS: This single-blinded randomized controlled trial was conducted in 200 American Society of Anesthesiologists physical status I, II, and III patients scheduled for elective/emergency surgery under general anesthesia. The patients were randomized into two groups: the Thermotherapy group- receiving an ice gel pack proximal to the intravenous cannula for 1 min, or the Lignocaine group-receiving 0.5 mg/kg of lignocaine administered intravenously, with occlusion proximal to the site of the intravenous cannula for 30 s. The primary objective was to compare the overall incidence of pain after propofol injection. The secondary objectives included the incidence of discomfort on the application of an ice gel pack, comparison of dose of propofol needed for induction, and hemodynamic changes at induction, between the two groups. RESULTS: Fourteen patients in the lignocaine group and 15 patients in the thermotherapy group reported pain. The incidence of pain and the distribution of pain scores were comparable among groups (p = 1.00). Patients of the lignocaine group required significantly less amount of propofol for induction as compared to the thermotherapy group (p = 0.001). CONCLUSION: Topical thermotherapy using an ice gel pack was not found superior to lignocaine pre-treatment in alleviating pain on injection of propofol injection. However, topical cold therapy using an ice pack remains a non-pharmacological technique that is easily available, reproducible, and cost-effective. Further studies are required to prove its equivalence to lignocaine pre-treatment. TRIAL REGISTRATION: CTRI (CTRI/2021/04/032950).