Classical cannabinoid receptors as target in cancer-induced bone pain: a systematic review, meta-analysis and bioinformatics validation.

To test the hypothesis that genetic and pharmacological modulation of the classical cannabinoid type 1 (CB1) and 2 (CB2) receptors attenuate cancer-induced bone pain, we searched Medline, Web of Science and Scopus for relevant skeletal and non-skeletal cancer studies from inception to July 28, 2022. We identified 29 animal and 35 human studies. In mice, a meta-analysis of pooled studies showed that treatment of osteolysis-bearing males with the endocannabinoids AEA and 2-AG (mean difference [MD] - 24.83, 95% confidence interval [95%CI] - 34.89, - 14.76, p < 0.00001) or the synthetic cannabinoid (CB) agonists ACPA, WIN55,212-2, CP55,940 (CB1/2-non-selective) and AM1241 (CB2-selective) (MD - 28.73, 95%CI - 45.43, - 12.02, p = 0.0008) are associated with significant reduction in paw withdrawal frequency. Consistently, the synthetic agonists AM1241 and JWH015 (CB2-selective) increased paw withdrawal threshold (MD 0.89, 95%CI 0.79, 0.99, p < 0.00001), and ACEA (CB1-selective), AM1241 and JWH015 (CB2-selective) reduced spontaneous flinches (MD - 4.85, 95%CI - 6.74, - 2.96, p < 0. 00001) in osteolysis-bearing male mice. In rats, significant increase in paw withdrawal threshold is associated with the administration of ACEA and WIN55,212-2 (CB1/2-non-selective), JWH015 and AM1241 (CB2-selective) in osteolysis-bearing females (MD 8.18, 95%CI 6.14, 10.21, p < 0.00001), and treatment with AM1241 (CB2-selective) increased paw withdrawal thermal latency in males (mean difference [MD]: 3.94, 95%CI 2.13, 5.75, p < 0.0001), confirming the analgesic capabilities of CB1/2 ligands in rodents. In human, treatment of cancer patients with medical cannabis (standardized MD - 0.19, 95%CI - 0.35, - 0.02, p = 0.03) and the plant-derived delta-9-THC (20 mg) (MD 3.29, CI 2.24, 4.33, p < 0.00001) or its synthetic derivative NIB (4 mg) (MD 2.55, 95%CI 1.58, 3.51, p < 0.00001) are associated with reduction in pain intensity. Bioinformatics validation of KEGG, GO and MPO pathway, function and process enrichment analysis of mouse, rat and human data revealed that CB1 and CB2 receptors are enriched in a cocktail of nociceptive and sensory perception, inflammatory, immune-modulatory, and cancer pathways. Thus, we cautiously conclude that pharmacological modulators of CB1/2 receptors show promise in the treatment of cancer-induced bone pain, however further assessment of their effects on bone pain in genetically engineered animal models and cancer patients is warranted.

Obesity is associated with improved progression-free survival in Microsatellite-Instability-High endometrial cancer treated with pembrolizumab.

OBJECTIVES: To determine the clinical predictors of response rate, progression-free survival (PFS), and overall survival (OS) to pembrolizumab in advanced or recurrent, mismatch repair deficient (MMRd) or Microsatellite Instability-High (MSI-H) endometrial adenocarcinomas. METHODS: A retrospective, single institution study was conducted among women with recurrent or advanced MMRd or MSI-H endometrial adenocarcinomas treated with single-agent pembrolizumab at our institution from 2017 to 2021. Logistic regression was used for univariable and multivariable analyses. PFS and OS were estimated using the methods of Kaplan and Meier and modeled via Cox proportional hazards regression. Log-rank test was used for intergroup comparisons based on body mass index (BMI). RESULTS: Among the 44 patients included in the analysis, the median BMI was 32.9 (range 18.5-51.8). Median cycles of pembrolizumab given was 11.5 (range 2-37). Median follow-up was 33 months (range 5-61) with a response rate of 63.6% and stable disease rate of 75%. When stratified by obesity status (BMI≥30), disease control rate was 59.8% in patients with a BMI < 30 and 85.2% in patients with a BMI≥30 patients (p = 0.05). On multivariable analysis, obesity was associated with increased rate of disease control (OR 4.03, 95%CI 1.09, 28) while prior smoking was associated with decreased rate of disease control (OR 0.18, 95%CI 0.03, 0.85). PFS was significantly increased among patients with a BMI≥30 (p = 0.03) but OS was similar (p = 0.5). CONCLUSION: In this retrospective study, obesity is associated with increased rates of disease control and improved PFS in patients treated with pembrolizumab for recurrent or advanced MMRd/MSI-H endometrial adenocarcinomas.

Posterior-scleritis: Case report of an uncommon immune-related adverse event in the treatment of advanced endometrial cancer.

As Immune checkpoint inhibitors are being expanded for use in gynecologic malignancies, rare immune-related adverse events are more frequently being reported. Here we describe a 63-year-old with Stage IIIB mismatch repair deficient uterine adenocarcinoma who underwent six cycles of carboplatin and paclitaxel with partial response but persistent disease. She was then started on single agent pembrolizumab. After six cycles of pembrolizumab, she developed bilateral vision changes and was diagnosed with posterior scleritis. Pembrolizumab was held and she was treated with oral prednisone, with rapid resolution of symptoms. One month after completion of prednisone, vision changes were again reported and she was restarted on a longer oral prednisone course. She then underwent definitive surgical management consisting of a total laparoscopic hysterectomy and bilateral salpingo-oophorectomy, with final pathology of benign endometrial hyperplasia. She has completed her steroid course without any symptoms. Given her complete pathologic response, she was subsequently placed into surveillance and is currently without evidence of disease. Prompt recognition and treatment of this rare immune-related adverse event led to the prevention of potential permanent, debilitating outcomes.

Methods of crop improvement and applications towards fortifying food security.

Agriculture has supported human life from the beginning of civilization, despite a plethora of biotic (pests, pathogens) and abiotic (drought, cold) stressors being exerted on the global food demand. In the past 50 years, the enhanced understanding of cellular and molecular mechanisms in plants has led to novel innovations in biotechnology, resulting in the introduction of desired genes/traits through plant genetic engineering. Targeted genome editing technologies such as Zinc-Finger Nucleases (ZFNs), Transcription Activator-Like Effector Nucleases (TALENs), and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) have emerged as powerful tools for crop improvement. This new CRISPR technology is proving to be an efficient and straightforward process with low cost. It possesses applicability across most plant species, targets multiple genes, and is being used to engineer plant metabolic pathways to create resistance to pathogens and abiotic stressors. These novel genome editing (GE) technologies are poised to meet the UN's sustainable development goals of "zero hunger" and "good human health and wellbeing." These technologies could be more efficient in developing transgenic crops and aid in speeding up the regulatory approvals and risk assessments conducted by the US Departments of Agriculture (USDA), Food and Drug Administration (FDA), and Environmental Protection Agency (EPA).

Quantum Chemical Investigation of Snow-Mercury Interactions and Their Implication of Mercury Deposition in the Arctic.

Elemental gaseous Hg is emitted into the atmosphere through various anthropogenic and natural processes. Mercury's different species and respective transport ranges, atmospheric physical and chemical transformations, and interaction with the earth's surfaces all contribute to the global cycling of toxic mercury. Under sunlight, halogens, ozone, and nitro species oxidize the emitted elemental Hg to gaseous Hg (II) molecules, which deposit onto the snow and ice surfaces in the Arctic. To investigate the fate of deposited mercury, a quantum chemical investigation was conducted using first-principles density functional theory (DFT) to analyze the interaction between various mercury molecules and snow clusters of differing sizes. Results show that all oxidized mercury molecules: XHgY, BrHgOX, BrHgXO XHgOH, XHgO2H, and XHgNO2, with X, Y = Cl, Br, and I atoms have thermodynamically stable interactions with snow clusters. Further, the adsorption energy of all mercury molecules increases with increasing size of snow clusters. Additionally, the orientations of deposited mercury molecules on the cluster surface also influence the mercury-snow interactions.

Fifteen-minute consultation: Recognition of sickle cell crises in the paediatric emergency department.

Children with sickle cell disease can develop life-threatening and painful crises that require prompt assessment and efficient management by healthcare professionals in the emergency or acute care setting. Due to migration patterns and improved survival rates in high-prevalence countries, there is an increased tendency to encounter these patients across the UK. These factors warrant regular revisions in sickle cell crisis management, along with education for medical personnel and patients to improve clinical care and patient management. The focus of this article is on the initial assessment and management of acute paediatric sickle cell complications in the emergency setting. Specific case studies, including acute pain crises, trauma, splenic sequestration, aplastic crises, acute chest syndrome, infection, avascular necrosis, osteomyelitis and stroke, are discussed. Due to the current COVID-19 pandemic, we have also reviewed specific concerns around this patient group.

Inside the story about the research and development of COVID-19 vaccines.

The ongoing coronavirus threat from China has spread rapidly to other nations and has been declared a global health emergency by the World Health Organization (WHO). The pandemic has resulted in over half of the world's population living under conditions of lockdown. Several academic institutions and pharmaceutical companies that are in different stages of development have plunged into the vaccine development race against coronavirus disease 2019 (COVID-19). The demand for immediate therapy and potential prevention of COVID-19 is growing with the increase in the number of individuals affected due to the seriousness of the disease, global dissemination, lack of prophylactics, and therapeutics. The challenging part is a need for vigorous testing for immunogenicity, safety, efficacy, and level of protection conferred in the hosts for the vaccines. As the world responds to the COVID-19 pandemic, we face the challenge of an overabundance of information related to the virus. Inaccurate information and myths spread widely and at speed, making it more difficult for the public to identify verified facts and advice from trusted sources, such as their local health authority or WHO. This review focuses on types of vaccine candidates against COVID-19 in clinical as well as in the preclinical development platform.

Toxicity and efficacy of the combination of pembrolizumab with recommended or reduced starting doses of lenvatinib for treatment of recurrent endometrial cancer.

OBJECTIVE: We reviewed our institutional data to evaluate toxicity and efficacy outcomes of pembrolizumab/lenvatinib in recurrent endometrial cancer in a "real-world" clinical setting and to compare the impact of reduced lenvatinib starting dose on outcomes. METHODS: Retrospectively, we reviewed toxicity, treatment responses, and survival outcomes of patients with recurrent endometrial cancer who received ≥1 cycle of pembrolizumab/lenvatinib. We compared subgroups based on lenvatinib starting dose (recommended [20 mg] vs reduced [<20 mg]) and histologic type. RESULTS: We analyzed 70 patients (recommended dose cohort, n = 16; reduced dose cohort, n = 54). The most common starting dose was 14 mg daily. Compared to the reduced dose cohort, the recommended dose cohort had a significantly higher mean number of lenvatinib dose reductions due to side effects (1.1 vs. 0.4; p = 0.003) and significantly shorter median time to treatment toxicity (1.3 vs. 3.7 days; p = 0.0001). Response rates did not differ significantly between the recommended and reduced dose cohorts (28.6% vs. 38.3%, respectively; p = 0.752). Two patients, both in the reduced dose cohort, had complete responses. Patients with carcinosarcoma histology had response and clinical benefit rates of 25% (3 of 12) and 58.3% (7 of 12), respectively. There were no differences between the 2 dose cohorts with respect to progression-free (p = 0.245) or overall survival (p = 0.858). CONCLUSION: In clinical practice, a lower starting dose of lenvatinib (14 mg daily) in combination with pembrolizumab was safe and efficacious in recurrent endometrial cancer. The combination produced responses in endometrial carcinosarcomas. Larger studies are required to validate these findings.

Measuring Stigma in Chronic Pain: Preliminary Investigation of Instrument Psychometrics, Correlates, and Magnitude of Change in a Prospective Cohort Attending Interdisciplinary Treatment.

Chronic pain is a potentially stigmatizing condition. However, stigma has received limited empirical investigation in people with chronic pain. Therefore, we examined the psychometric properties of a self-report questionnaire of stigma in people with chronic pain attending interdisciplinary treatment. Secondarily, we undertook an exploratory examination of the magnitude of change in stigma associated with interdisciplinary treatment in a prospective observational cohort. Participants attending interdisciplinary treatment based on acceptance and commitment therapy completed the Stigma Scale for Chronic Illness 8-item version (SSCI-8; previously developed and validated in neurological samples), and measures of perceived injustice, pain acceptance, and standard pain outcomes before (n = 300) and after treatment (n = 247). A unidimensional factor structure and good internal consistency were found for the SSCI-8. Total SSCI-8 scores were correlated with pain intensity, indices of functioning, and depression in bivariate analyses. Stigma scores were uniquely associated with functioning and depression in multiple regression analyses controlling for demographic factors, pain intensity, pain acceptance, and perceived injustice at baseline. SSCI-8 total scores did not significantly improve after treatment, although an exploratory subscale analysis showed a small improvement on internalized stigma. In contrast, scores on perceived injustice, pain acceptance, and pain outcomes improved significantly. Taken together, these data support the reliability and validity of the SSCI-8 for use in samples with chronic pain. Further research is needed optimize interventions to target stigma at both the individual and societal levels. PERSPECTIVE: This study supports the use of the SSCI-8 to measure stigma in chronic pain. Stigma is uniquely associated with worse depression and pain-related disability. Research is needed to identify how to best target pain-related stigma from individual and societal perspectives.

Age-related changes in the marmoset gut microbiome.

The gut microbiome is known to play a significant role in human health but its role in aging remains unclear. The objective of this study was to compare the gut microbiome composition between young adult and geriatric non-human primates (marmosets) as a model of human health and disease. Stool samples were collected from geriatric (8+ years) and young adult males (2-5 years). Stool 16S ribosomal RNA V4 sequences were amplified and sequenced on the Illumina MiSeq platform. Sequences were clustered into operational taxonomic units and classified via Mothur's Bayesian classifier referenced against the Greengenes database. A total of 10 young adult and 10 geriatric marmosets were included. Geriatric marmosets had a lower mean Shannon diversity compared with young marmosets (3.15 vs. 3.46; p = 0.0191). Geriatric marmosets had a significantly higher mean abundance of Proteobacteria (0.22 vs. 0.09; p = 0.0233) and lower abundance of Firmicutes (0.15 vs. 0.19; p = 0.0032) compared with young marmosets. Geriatric marmosets had a significantly higher abundance of Succinivibrionaceae (0.16 vs. 0.01; p = 0.0191) and lower abundance of Porphyromonadaceae (0.07 vs. 0.11; p = 0.0494). In summary, geriatric marmosets had significantly altered microbiome diversity and composition compared with young adult marmosets. Further studies are needed to test microbiome-targeted therapies to improve healthspan and lifespan.

Implementation of postdischarge follow-up telephone calls at a comprehensive cancer center.

PURPOSE: The development and implementation of a pharmacy-driven, postdischarge follow-up telephone call program to assess medication adherence, provide education, and address medication-related concerns are discussed. SUMMARY: Many readmissions are avoidable through effective discharge planning and patient follow-up after hospitalization. However, there is limited information on how to effectuate this process. To address this barrier, a team consisting of a clinical pharmacy specialist, a clinical pharmacy manager, a postgraduate year 1 pharmacy resident, and an education specialist at The University of Texas MD Anderson Cancer Center collaborated to create a postdischarge telephone call program within a transitions-of-care (TOC) pilot program. Various education and training materials were created to ensure trainees were competent. As of February 2016, 23 outpatient pharmacists and students have completed training, earning a median pretest and posttest score of 6 and 9, respectively, out of 10. There have been 206 calls completed; 150 patients (73%) were successfully reached, and 20 patients (9%) declined the telephone call. Medication adherence assessed during the telephone follow-up identified that 134 patients (89%) received their new medications within 72 hours, and 87 patients (58%) were recognized as having one or more discrepancies. CONCLUSION: Developing a TOC program similar to this pilot program requires several resources including time, collaboration, and support from the management team. Pharmacy is well positioned to complete an accurate medication review and conduct postdischarge telephone calls to address medication-related issues. By providing these services, patients will receive continuity of care and positively impact emergency room visitation rates and hospital readmission rates.

Updates in the Management of Cephalosporin-Resistant Gram-Negative Bacteria.

Resistance to cephalosporins is now common among Gram-negative bacterial infections, including those caused by the Enterobacteriaceae and Pseudomonas aeruginosa, posing a major threat to public health. As resistance to the traditional drugs of choice for these infections, carbapenems, has also become increasingly common, interest in cefepime and piperacillin-tazobactam as carbapenem-sparing alternatives has increased. Additionally, the availability of the novel ß-lactam-ß-lactamase inhibitor combinations ceftolozane-tazobactam and ceftazidime-avibactam has added to the antimicrobial armamentarium available to treat these multidrug-resistant infections. Here, we review the recent literature on the use of carbapenem-sparing alternatives and highlight the potential utility of novel antimicrobials.

Oxaliplatin-induced immune-mediated cytopenias: a case report and literature review.

Oxaliplatin is a third-generation platinum antineoplastic agent that commonly causes diarrhea, nausea, vomiting, myelosuppression, and peripheral neuropathy. Less common adverse effects that are increasingly being reported include acute immune-mediated thrombocytopenia, hemolytic anemia, and pancytopenia. Here, we report a patient case of suspected oxaliplatin-induced immune-mediated thrombocytopenia and a thorough literature evaluation of acute oxaliplatin-induced immune-mediated thrombocytopenia, hemolytic anemia, and pancytopenia that has yet to be reported until now. There have been 39 previously published reports of these cytopenic events with a median number of 16 treatment cycles prior to presentation. Patients experiencing unusual signs and symptoms such as chills, rigors, fever, back pain, abdominal pain, ecchymosis, hematemesis, hematuria, dark urine, hematochezia, petechiae, epistaxis, or mental status changes during or shortly after an oxaliplatin infusion should have complete blood counts ordered and evaluated promptly.

Whole exome re-sequencing implicates CCDC38 and cilia structure and function in resistance to smoking related airflow obstruction.

Chronic obstructive pulmonary disease (COPD) is a leading cause of global morbidity and mortality and, whilst smoking remains the single most important risk factor, COPD risk is heritable. Of 26 independent genomic regions showing association with lung function in genome-wide association studies, eleven have been reported to show association with airflow obstruction. Although the main risk factor for COPD is smoking, some individuals are observed to have a high forced expired volume in 1 second (FEV1) despite many years of heavy smoking. We hypothesised that these "resistant smokers" may harbour variants which protect against lung function decline caused by smoking and provide insight into the genetic determinants of lung health. We undertook whole exome re-sequencing of 100 heavy smokers who had healthy lung function given their age, sex, height and smoking history and applied three complementary approaches to explore the genetic architecture of smoking resistance. Firstly, we identified novel functional variants in the "resistant smokers" and looked for enrichment of these novel variants within biological pathways. Secondly, we undertook association testing of all exonic variants individually with two independent control sets. Thirdly, we undertook gene-based association testing of all exonic variants. Our strongest signal of association with smoking resistance for a non-synonymous SNP was for rs10859974 (P = 2.34 × 10(-4)) in CCDC38, a gene which has previously been reported to show association with FEV1/FVC, and we demonstrate moderate expression of CCDC38 in bronchial epithelial cells. We identified an enrichment of novel putatively functional variants in genes related to cilia structure and function in resistant smokers. Ciliary function abnormalities are known to be associated with both smoking and reduced mucociliary clearance in patients with COPD. We suggest that genetic influences on the development or function of cilia in the bronchial epithelium may affect growth of cilia or the extent of damage caused by tobacco smoke.

Training New-Hire Medical Information Specialists in the Pharmaceutical Industry: A Benchmarking Survey.

Most pharmaceutical and biotechnology companies have a medical information (MI) department staffed by medical information specialists (MISs); to ensure that MISs perform their role in an accurate and compliant manner, companies must have robust training processes in place. The primary objective of this study was to benchmark the training processes for new-hire MISs in the pharmaceutical industry as well as their training preferences. Nineteen respondents from 19 companies completed a web-based survey, which resulted in a 41.3% response rate. These companies represented a variety of MI department sizes and number of products supported. Eighty-four percent (16/19) of companies had structured new-hire training processes in place. Approximately two-thirds of all respondents preferred live training on new-hire training topics. After completion of new-hire training, several companies (10/18) offered ongoing refresher training to their MISs. The results indicate that companies may benefit from having structured new-hire training procedures and tailoring training to MIS learning preferences.

Development and validation of a RP-HPLC method for the estimation of netilmicin sulfate and its related substances using charged aerosol detection.

Netilmicin is a semi-synthetic aminoglycoside antibiotic used against a broad spectrum of Gram-negative bacteria. A reversed-phase high-performance liquid chromatographic method has been developed to determine the composition of netilmicin sulfate and to estimate its related substances without pre- or post-column derivatization. A UV detector cannot be used to detect low levels of known and unknown related substances of netilmicin, as it has only a weak UV chromophore. A charged aerosol detector was used instead to obtain the high sensitivity that was necessary for the intended purpose of the method. This method can separate all related substances of netilmicin. A (10 cm x 4.6 mm) pentafluorophenyl high-performance liquid chromatographic column from Restek was used with a mobile phase consisting of (A) pentafluoropropionic acid-water-acetonitrile (0.1:96:4, v/v/v) and (B) trifluoroacetic acid-water-acetonitrile (1:96:4, v/v/v).