Evidence for the use of cannabis-based medicines in osteoarthritis: a scoping review.

The purpose of this study was to conduct a scoping review to describe the evidence on the efficacy and safety of using cannabis-based medicines for osteoarthritis. The review was conducted following the framework proposed by Arksey and O'Malley and reported following PRISMA extension for scoping reviews guidelines. We conducted a comprehensive search across various databases including MEDLINE, Embase, Cochrane Library, CINAHL, Scopus, and Proquest, spanning from inception of each database to March 2023. We retrieved 2533 citations, and after deduplication, title and abstract screening, and full-text screening, 10 articles were included for analysis. These studies were composed of randomized-controlled trials (n = 4/10), cross-sectional surveys (n = 3/10), case studies (n = 2/10), and a cohort study (n = 1/10). Evidence for using cannabis-based medicines was mixed, with just 60% (n = 6/10) of included studies reporting statistically significant improvements in pain. Studies with larger samples sizes and longer durations of exposure did not find significant benefits for pain. The few adverse effects reported were generally mild and affected a minority of participants. Several studies also discovered that cannabis-based medicines were associated with a reduction in opioid use. Currently available data on the use of cannabis-based medicines in osteoarthritis is insufficient to make recommendations. Future research should address concerns regarding small sample sizes and short treatment durations to provide a more robust evidence base. Key Points • Current evidence remains mixed; studies that found a positive benefit with using cannabis-based medicines had limitations with small sample sizes and short durations of exposure • The use of cannabis-based medicines in osteoarthritis appears to be generally well tolerated, adverse effects are mild and experienced by a minority of participants • Cannabis-based medicines may decrease the use of opioids in patients with osteoarthritis • Future research should address the gaps in long-term efficacy and safety data.

Nodular fasciitis of the orbit: rapid growth phase post iatrogenic incisional trauma.

Nodular fasciitis (NF) is a benign, reactive, myofibroblastic proliferative solitary lesion that commonly develops in the subcutaneous or superficial fascia. We present a case of a 35-year-old male with a rapidly enlarging upper eyelid mass postiatrogenic incisional trauma. Subsequent en toto excisional biopsy demonstrated NF. Given the rapid clinical course of this patient and the reactive nature of NF, we hypothesize that the initial incisional trauma likely incited an inflammatory response resulting in rapid proliferation and growth of the lesion. NF accounts for <1% of all orbital lesions, and is often a clinically and pathologically difficult diagnosis to make given its propensity to mimic other benign and malignant conditions. Therefore, we recommend that en toto biopsies of orbital lesions in this anatomical area be performed rather than incisional biopsies.

Discovery of quinazoline HPK1 inhibitors with high cellular potency.

Hematopoietic progenitor kinase 1 (HPK1) is regarded as a highly validated target in pre-clinical immune oncology. HPK1 has been described as regulating multiple critical signaling pathway in both adaptive and innate cells. In support of this role, HPK1 KO T cells show enhanced sensitivity to TCR activation and HPK1 KO mice display enhanced anti-tumor activity. Taken together, inhibition of HPK1 has the potential to induce enhanced anti-tumor immune response. Herein, we described the discovery of highly potent HPK1 inhibitors starting form a weak HTS hit. Using a structure-based drug design, HPK1 inhibitors exhibiting excellent cellular single-digit nanomolar potency in both proximal (pSLP76) and distal (IL-2) biomarkers along with sustained elevation of IL-2 cytokine secretion were discovered.

Evaluation of Lineage/Site-specific Nuclear Immunohistochemical Markers SATB2, Cyclin D1, SALL4, and BCOR in High-grade Endometrial Carcinomas.

Poorly differentiated malignant neoplasms involving the gynecologic tract routinely include a poorly differentiated endometrial carcinoma (EC) in the differential diagnosis. Some nuclear lineage/site-specific immunohistochemical markers are utilized in this diagnostic setting including SATB2, cyclin D1, SALL4, and BCOR, but their specificity and use in small samples are not clear across the spectrum of ECs. Cases of undifferentiated/dedifferentiated endometrial carcinomas (UEC/DDEC), clear cell carcinoma (CCC), uterine serous carcinoma (USC), FIGO grade 3 endometrial endometrioid carcinoma (EEC), and uterine carcinosarcoma (UCS) were identified and diagnoses confirmed. Whole-section immunohistochemical stains for SATB2, cyclin D1, SALL4, BCOR, and PAX8 were performed. A total of 113 cases were utilized: 15 CCC, 26 EEC, 19 UCS, 22 USC, and 31 UEC/DDEC. Cases were distributed across both low (49%) and high (51%) FIGO clinical stages. SATB2 was expressed by UCS (8/19, 42%), EEC (10/26, 38%), UEC/DDEC (11/30, 37%), and USC (6/22, 27%). Cyclin D1 was expressed by EEC (24/26, 92%), USC (17/22, 77%), UEC/DDEC (15/20 EEC component, 75%; 22/30 UEC, 73%), UCS (10/16 carcinoma, 63%; 11/19 sarcoma, 58%), and CCC (8/15, 53%). SALL4 was expressed most frequently by UEC/DDEC (12/30, 40%), but also USC (7/22, 32%), EEC (5/26, 19%), and UCS (4/16 carcinoma, 25%; 3/19 sarcoma, 16%). BCOR was expressed at low levels in 2 USC, 2 UEC/DDEC, and 2 UCS. PAX8 was generally positive but showed lower expression in UEC/DDEC (17/30, 57%) and in the sarcomatous portions of UCS (6/19, 32%). SATB2, cyclin D1, SALL4, and BCOR stain variable numbers of poorly-differentiated EC and must be carefully interpreted within morphologic and clinical context.

Cervical cancer patient reported gastrointestinal outcomes: intensity/volumetric modulated vs. 3D conformal radiation therapy.

OBJECTIVE: To evaluate gastrointestinal (GI) patient reported outcomes (PROs) in cervical cancer patients treated with definitive radiotherapy (RT), comparing 3D conformal RT (3DCRT) vs. intensity modulated/volumetric modulated arc therapy (IMRT/VMAT). METHODS: An analysis of patients treated with definitive RT between 2015-2018 was performed. GI PROs were prospectively collected at baseline, during RT (acute), ≤12 weeks after RT (subacute), and >12 weeks after RT (late). GI PROs evaluated three symptom domains: bowel problems (BPs), bowel bother (BB), and abdominal problems (APs). Multiple linear regression analysis was performed to investigate associations between mean changes of symptom scores with clinical and dosimetric variables. RESULTS: The cohort included 167 patients. A total of 100 (60%) patients were treated with IMRT/VMAT and 67 (40%) with 3DCRT. In the subacute phase, the mean change of symptom scores from baseline in 3DCRT vs. IMRT/VMAT were +0.9 vs. -1.15 (p=0.004) for BP, +2.18 vs. -0.10 (p=0.019) for BB, and +1.41 vs. -0.38 (p=0.021) for AP. Likewise, in the late phase, mean changes were +0.72 vs. -0.82 (p=0.014) for BP, +1.98 vs. -0.03 (p=0.008) for BB, and +1.29 vs. -0.31 (p<0.001) for AP. On multiple linear regression, use of 3DCRT vs. IMRT/VMAT was associated with greater mean changes in subacute BP (p=0.023) and late phase AP (p=0.019). A higher small bowel V50Gy was associated increased symptom scores in late AP (p=0.012). CONCLUSION: 3DCRT was associated with significantly greater worsening of GI PRO symptom scores in the subacute and late phase. These data support the ongoing use of IMRT/VMAT in routine practice.

Small bowel obstruction precipitated by intussusception of Meckel's diverticulum.

Small bowel obstruction (SBO) secondary to intussusception of Meckel's diverticulum (MD) is a rare cause of acute abdominal pain that may warrant urgent surgical treatment. Volvulus or intussusception of the small bowel with presence of MD as the lead point is the most commonly reported etiology of Meckel's related obstructions. We report an interesting case of a small bowel obstruction caused by the intussusception of an MD within its own lumen. The case involves a 30-year-old male who presented to the emergency room with acute, severe abdominal pain with an abdominal computed tomography (CT) showing a distal high-grade SBO. Decision was made to take the patient to the operating room urgently due to his clinical examination and radiologic imaging, specifically CT scan. Diagnostic laparoscopy was performed and subsequently converted to an exploratory laparotomy, which revealed the intussuscepted MD with focal necrosis into the distal small bowel causing an SBO. A segmental small bowel resection with hand sewn primary anastomosis was performed. The case presents an interesting challenge in deciding when to take a patient with an SBO to the operating room versus initial conservative management and what the treatment should be if an MD is encountered. In addition, the case emphasizes the importance of history and physical exam findings in coordination with radiologic imaging in helping to make appropriate decisions in a timely manner for operative vs conservative management of an SBO. It reminds us that, Meckel's diverticulum, although less commonly the cause of a small bowel obstruction in the adult population, needs to be on the differential diagnosis and we need to have a high clinical suspicion for this possibility to ensure appropriate treatment in a timely manner.

Clinical factors associated with positive corneal culture in suspected microbial keratitis.

AIMS: Determine demographic and clinical characteristics associated with positive culture in suspected microbial keratitis. METHODS: Retrospective audit of patients that had corneal scrapings between October 1999-September 2004 at Princess Alexandra Hospital. Clinical information was gathered from medical records, smear and culture results from the local microbiology database. Univariate and multivariate analyses of variables associated with positive cultures and calculation of population attributable risk percentage (PAR). RESULTS: Univariate analysis showed that positive cultures were associated with patients over 60 years (81% vs 55%; p < 0.001), presenting visual acuity (VA) of 6/24 or worse (74% vs 57%; p = 0.012) or contact lens-related keratitis (CLK 77% vs 62%; p = 0.08). Analysis of patients' clinical presentation showed that positive culture was associated with a central epithelial defect (74% vs 57%; p = 0.012), anterior chamber reaction of 2 + cells or worse (73% vs 56%; p = 0.03), an epithelial defect of 2 mm or more in diameter (71% vs 50%; p = 0.006) or no prior treatment with antibiotics (68% vs 56%; p = 0.053). Multivariate analysis showed the independent variables associated with positive cultures were VA of 6/24 or worse on presentation, contact lens-related keratitis, age greater than 60 years, an anterior chamber reaction of 2 + cells or worse and no prior treatment with antibiotics. The factor with the highest attributable risk (PAR%) for a positive corneal scraping was VA of 6/24 or worse on presentation (21%). CONCLUSIONS: In this series positive cultures were associated with poor presenting VA contact lens keratitis (CLK), older age, anterior chamber reaction and no prior treatment with antibiotics.

Development of Tyrphostin Analogues to Study Inhibition of the Mycobacterium tuberculosis Pup Proteasome System*.

Tuberculosis is a global health problem caused by infection with the Mycobacterium tuberculosis (Mtb) bacteria. Although antibiotic treatment has dramatically reduced the impact of tuberculosis on the population, the existence and spreading of drug resistant strains urgently demands the development of new drugs that target Mtb in a different manner than currently used antibiotics. The prokaryotic ubiquitin-like protein (Pup) proteasome system is an attractive target for new drug development as it is unique to Mtb and related bacterial genera. Using a Pup-based fluorogenic substrate, we screened for inhibitors of Dop, the Mtb depupylating protease, and identified I-OMe-Tyrphostin AG538 (1) and Tyrphostin AG538 (2). The hits were validated and determined to be fast-reversible, non-ATP competitive inhibitors. We synthesized >25 analogs of 1 and 2 and show that several of the synthesized compounds also inhibit the depupylation actions of Dop on native substrate, FabD-Pup. Importantly, the pupylation activity of PafA, the sole Pup ligase in Mtb, was also inhibited by some of these compounds.

Outcomes of stereotactic body radiotherapy 60 Gy in 8 fractions when prioritizing organs at risk for central and ultracentral lung tumors.

BACKGROUND: For stereotactic body radiotherapy (SBRT) to central (C) and ultracentral (UC) lung tumors, our provincial practice has been to prioritize organs at risk (OARs) constraints by compromising target volume coverage if needed. The objectives are to report the treatment's efficacy and safety. METHODS: We conducted a retrospective analysis of all provincial patients who underwent SBRT at 60Gy in 8 fractions to C and UC lung tumors, from 2013 to 2017. RESULTS: Ninety-eight lesions were treated, 57 (58.2%) C and 41 (41.8%) UC. The median follow-up was 22.9 months (range 2.5-64.8 months). The 1- and 3-year local control (LC) was 97.8 and 84.5% respectively, with no differences between C and UC groups (p = 0.662). Fifty-three (54.1%) cases had optimal dose coverage (V60Gy ITV&PTV > 95%), 29 (29.6%) had compromised PTV coverage (V60Gy ITV > 95%/PTV < 95%), and 16 (16.3%) had both compromised ITV and PTV coverage (V60Gy ITV&PTV < 95%). No significant difference in LC was detected at 2 years between the 3 groups (95.6, 91.8 and 90.9%, p = 0.717). There were 3 episodes of grade 3 toxicity in the C group (2 dyspnea, 1 pneumonitis) and 2 in the UC group (1 dyspnea, 1 hemoptysis). There were no gr4/5 toxicities. On multivariable Cox regression analysis, ITV size was found to be a predictor for LC (p = 0.001). CONCLUSIONS: SBRT at 60Gy in 8 fractions achieves high rates of LC with low risks of significant toxicities, even if target volume coverage is reduced to meet OARs constraints.

Characterization of Guided Entry of Tail-Anchored Proteins 3 Homologues in Mycobacterium tuberculosis.

We characterized an operon in Mycobacterium tuberculosis, Rv3679-Rv3680, in which each open reading frame is annotated to encode "anion transporter ATPase" homologues. Using structure prediction modeling, we found that Rv3679 and Rv3680 more closely resemble the guided entry of tail-anchored proteins 3 (Get3) chaperone in eukaryotes. Get3 delivers proteins into the membranes of the endoplasmic reticulum and is essential for the normal growth and physiology of some eukaryotes. We sought to characterize the structures of Rv3679 and Rv3680 and test if they have a role in M. tuberculosis pathogenesis. We solved crystal structures of the nucleotide-bound Rv3679-Rv3680 complex at 2.5 to 3.2 Å and show that while it has some similarities to Get3 and ArsA, there are notable differences, including that these proteins are unlikely to be involved in anion transport. Deletion of both genes did not reveal any conspicuous growth defects in vitro or in mice. Collectively, we identified a new class of proteins in bacteria with similarity to Get3 complexes, the functions of which remain to be determined.IMPORTANCE Numerous bacterial species encode proteins predicted to have similarity with Get3- and ArsA-type anion transporters. Our studies provide evidence that these proteins, which we named BagA and BagB, are unlikely to be involved in anion transport. In addition, BagA and BagB are conserved in all mycobacterial species, including the causative agent of leprosy, which has a highly decayed genome. This conservation suggests that BagAB constitutes a part of the core mycobacterial genome and is needed for some yet-to-be-determined part of the life cycle of these organisms.