Anti-Staphylococcus aureus potential of compounds from Ganoderma sp.: A comprehensive molecular docking and simulation approaches.

In this study, a series of secondary metabolites from Ganoderma sp. were screened against Staphylococcus aureus protein targets, including as phosphotransacetylase, clumping factor A, and dihydrofolate reductase, using molecular docking simulations. The chemicals that showed the strongest binding energy with the targeted proteins were ganodermanontriol, lucidumol B, ganoderic acid J, ergosterol, ergosterol peroxide, 7-oxoganoderic acid Z, ganoderic acid AM1, ganosinoside A, ganoderic acid D, and 24R-ergosta-7,2E-diene-3ß,5α,6ß-triol. Interestingly, ganosinoside A showed the greatest affinity for the protein clumping factor A, a result validated by molecular dynamic simulation. Additionally, three natural Ganoderma sp. Strains as Ganoderma lingzhi VNKKK1903, Ganoderma lingzhi VNKK1905A2, and Amauroderma subresinosum VNKKK1904 were collected from Kon Ka Kinh National Park in central land of Vietnam and evaluated for their antibacterial activity against Staphylococcus aureus using an agar well diffusion technique. These results suggest that the fungal extracts and secondary metabolites may serve as valuable sources of antibiotics against Staphylococcus aureus. These findings provided an important scientific groundwork for further exploration of the antibacterial mechanisms of compounds derived from Ganoderma sp. in future research.

Preparations and characterizations of effervescent granules containing azithromycin solid dispersion for children and elder: Solubility enhancement, taste-masking, and digestive acidic protection.

Azithromycin, a macrolide antibiotics, is one of the frequently used drugs in the children and elder. However, due to these population difficulty in swallowing and inefficient absorption, and azithromycin inherent poor solubility, bitter taste, and instability in the stomach acidic condition, it is a challenge to reach high oral bioavailability of this drug. To overcome these issues, we developed and characterized the effervescent granules containing azithromycin solid dispersion. Firstly, the solid dispersion was prepared, employing both wet grinding and solvent evaporation methods, with different types/amounts of polymers. The optimal solid dispersion with ß-cyclodextrin at a drug:polymer ratio of 1:2 (w/w), prepared by the solvent evaporation method, significantly enhanced the azithromycin solubility 4-fold compared to the free drug, improved its bitterness from "bitter" to "normal", possessed intermolecular bonding between the drug and polymer, and transformed the azithromycin molecules from crystalline to amorphous state. Secondly, the effervescent granules incorporating the solid dispersion were formulated with varied excipients of sweeteners, gas-generators, pH modulators, and glidants/lubricants. The optimal formula satisfied all the properties stated in the Vietnamese Pharmacopoeia. In summary, the final effervescent granules product could be further investigated in in-vivo and in clinical settings to become a potential azithromycin delivery system with high bioavailability for the children and elder.

Clinical Utility of Genomic Recurrence Risk Stratification in Early, Hormone-Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer: Real-World Experience.

BACKGROUND: RNA-based genomic risk assessment estimates chemotherapy benefit in patients with hormone-receptor positive (HR+)/Human Epidermal Growth Factor 2-negative (ERBB2-) breast cancer (BC). It is virtually used in all patients with early HR+/ERBB2- BC regardless of clinical recurrence risk. PATIENTS AND METHODS: We conducted a retrospective chart review of adult patients with early-stage (T1-3; N0; M0) HR+/ERBB2- BC who underwent genomic testing using the Oncotype DX (Exact Sciences) 21-genes assay. Clinicopathologic features were collected to assess the clinical recurrence risk, in terms of clinical risk score (CRS) and using a composite risk score of distant recurrence Regan Risk Score (RRS). CRS and RRS were compared to the genomic risk of recurrence (GRS). RESULTS: Between January 2015 and December 2020, 517 patients with early-stage disease underwent genomic testing, and clinical data was available for 501 of them. There was statistically significant concordance between the 3 prognostication methods (P < 0.01). Within patients with low CRS (n = 349), 9.17% had a high GRS, compared to 8.93% in patients with low RRS (n = 280). In patients with grade 1 histology (n = 130), 3.85% had a high GRS and 68.46% had tumors > 1 cm, of whom only 4.49% had a high GRS. Tumor size > 1cm did not associate with a high GRS. CONCLUSION: Genomic testing for patients with grade 1 tumors may be safely omitted, irrespective of size. Our finds call for a better understanding of the need for routine genomic testing in patients with low grade/low clinical risk of recurrence.

Cold Plasmamed Beam as a Supporting Treatment of Soft Tissue Injuries in Severe Covid-19 Patients: A Preliminary Report.

Background: Cold plasma has many characteristics that allow for effective wound healing. Due to its efficacy, we have applied it in treating patients with severe Covid-19 who have soft tissue skin lesions and diseases including burns, pressure ulcers, shingles, and contact or atopic dermatitis. This study aims to assess the general characteristics of Covid-19 patients with soft tissue lesions and to conduct a fundamental evaluation of the efficacy of cold plasmamed beams in treating soft tissue wounds in patients with severe Covid-19. Methods: This prospective study was conducted on 20 severe Covid-19 patients with soft tissue lesions at the Intensive Care Center for Covid-19 of Hue Central Hospital in Ho Chi Minh City from September 25 to November 11, 2021. These patients was performed cold plasma irradiation at any stage of wound progression, including new injuries and chronic wounds. Results: Among 915 severe Covid-19 patients treated at our center, 20 patients had soft tissue lesions. Grade I, II, and III pressure ulcers accounted for 70% of the 20 cases of soft tissue lesions and 1.53% of the total patients at the time of the survey. Pressure ulcers were present in only 0.55% of patients (5/915 patients). Eleven out of 20 patients (55.0%) had lesions before admission, and 9 (45.0%) had lesions that appeared after admission. After 14 days of treatment, 14/20 patients had complete epithelialization (70%), and in 18/20 patients, wound exudation had ceased. The wounds became painless; after 3 weeks, the rashes had completely disappeared. Conclusion: The study emphasizes that irradiation with cold plasma contributes to the wound healing process.

Liquid Biopsy-based Precision Therapy in Patients with Advanced Solid Tumors: A Real-world Experience from a Community-based Oncology Practice.

BACKGROUND: Liquid biopsy testing offers a significant potential in selecting signal-matched therapies for advanced solid malignancies. The feasibility of liquid biopsy testing in a community-based oncology practice, and its actual impact on selecting signal-matched therapies, and subsequent survival effects have not previously been reported. PATIENTS AND METHODS: A retrospective chart review was conducted on adult patients with advanced solid cancer tested with a liquid-biopsy assay between December 2018 and 2019, in a community oncology practice. The impact of testing on treatment assignment and survival was assessed at 1-year follow-up. RESULTS: A total of 178 patients underwent testing. A positive test was reported in 140/178 patients (78.7%), of whom 75% had an actionable mutation. The actual overall signal-based matching rate was 17.8%. While 85.7% of patients with no actionable mutation had a signal-based clinical trial opportunity, only 10% were referred to a trial. Survival analysis of lung, breast, and colorectal cancer patients with actionable mutations who received any therapy (n = 66) revealed a survival advantage for target-matched (n = 22) compared to unmatched therapy (n = 44): patients who received matched therapy had significantly longer progression-free survival (PFS) (mPFS: 12 months; 95%CI, 10.6-13.4 vs. 5.0 months; 95%CI, 3.4-6.6; P = .029), with a tendency towards longer overall survival (OS) (mOS: 15 months; 95%CI, 13.5-16.5 vs. 13 months; 95%CI: 11.3-14.7; P = .087). CONCLUSIONS: Implementation of liquid biopsy testing is feasible in a US community practice and impacts therapeutic choices in patients with advanced malignancies. Receipt of liquid biopsy-generated signal-matched therapies conferred added survival benefits.

Solitary, Late Metastatic Recurrence of Renal Cell Carcinoma to the Pancreas: A Case Report.

Renal cell carcinoma (RCC) accounts for 3% of all adult malignancies and is known for metastatic initial presentation, unpredictable metastatic pathway, and late recurrence post-curative resection. We report a case of solitary late metastatic renal cell carcinoma to the pancreas more than 10 years after radical nephrectomy. A high index of suspicion must be maintained to detect RCC late recurrence and metastasis to rare and atypical locations. A lifelong follow-up is recommended.

Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type: A Case Report.

Primary cutaneous diffuse large B-cell lymphoma, leg type, is an exceedingly rare and aggressive variant of primary cutaneous lymphoma. An 84-year-old male presented to an oncologist for new skin lesions on his abdomen and right thigh. Excisional biopsy followed by histopathology and immunohistochemistry confirmed the diagnosis of primary cutaneous diffuse large B-cell lymphoma, leg type. His clinical course was complicated by multiple relapses and refractory disease. Ultimately, he achieved complete response with fourth-line ibrutinib therapy. Due to the contentious nature of this disease, poor prognosis, and higher rates of recurrence, prompt identification and aggressive treatment are recommended. Given the different cellular pathways and genomic alterations identified in its carcinogenesis, various chemotherapy regimens and targeted immunotherapies have emerged as potential therapeutic options to halt disease progression and prevent future relapses.

E3611-A Randomized Phase II Study of Ipilimumab at 3 or 10 mg/kg Alone or in Combination with High-Dose Interferon-α2b in Advanced Melanoma.

PURPOSE: Interferon-α favors a Th1 shift in immunity, and combining with ipilimumab (ipi) at 3 or 10 mg/kg may downregulate CTLA4-mediated suppressive effects, leading to more durable antitumor immune responses. A study of tremelimumab and high-dose interferon-α (HDI) showed promising efficacy, supporting this hypothesis. PATIENTS AND METHODS: E3611 followed a 2-by-2 factorial design (A: ipi10+HDI; B: ipi10; C: ipi3+HDI; D: ipi3) to evaluate (i) no HDI versus HDI (across ipilimumab doses) and (ii) ipi3 versus ipi10 (across HDI status). We hypothesized that median progression-free survival (PFS) would improve from 3 to 6 months with HDI versus no HDI and with ipi10 versus ipi3. RESULTS: For eligible and treated patients (N = 81) at a median follow-up time of 29.8 months, median PFS was 4.4 months [95% confidence interval (CI), 2.7-8.2] when ipilimumab was used alone and 7.5 months (95% CI, 5.1-11.0) when HDI was added. Median PFS was 3.8 months (95% CI, 2.6-7.5) with 3 mg/kg ipilimumab and 6.5 months (95% CI, 5.1-13.5) with 10 mg/kg. By study arm, median PFS was 8.0 months (95% CI, 2.8-20.2) in arm A, 6.2 months (95% CI, 2.7-25.7) in B, 5.7 months (95% CI, 1.5-11.1) in C, and 2.8 months (95% CI, 2.6-5.7) in D. The differences in PFS and overall survival (OS) did not reach statistical significance. Adverse events were consistent with the known profiles of ipilimumab and HDI and significantly higher with HDI and ipi10. CONCLUSIONS: Although PFS was increased, the differences resulting from adding interferon-α or a higher dose of ipilimumab did not reach statistical significance and do not outweigh the added toxicity risks.

The Effect of Pembrolizumab in Absence of Programmed Death 1 Receptor.

Tumor therapy has evolved greatly since the discovery of immunotherapies. New therapies permit targeted approach with less side effects. Immunotherapies target specific components recognized on tumor cells, such as Programmed death-1 (PD-1). Overexpression of PD-1 markers in solid gastrointestinal tumors is a consequence of deficiency in DNA mismatch repair mechanism. Pembrolizumab is an example of immunotherapy targeting PD-1. Pembrolizumab binding of PD-1 helps the immune system recognize tumor cells and initiate destruction cascade. We present a case of a PD-1 negative appendiceal tumor responding to pembrolizumab.

Metastatic Breast Cancer with BRCA Mutation Discovered By Next-Generation Sequencing Responding to Olaparib.

Breast cancer susceptibility genes 1 and 2 (BRCA1 and BRCA2) mutations are associated with hereditary breast and ovarian cancer syndromes (HBOC). However, certain individuals with breast cancer do not meet high-risk factors for hereditary breast cancer screening based on age, family history, and biology of malignancy. We present a patient with relapsed breast cancer who developed progressive disease with significant tumor burden causing a recurrent pleural effusion. Next-generation sequencing (NGS) done on a tumor biopsy was positive for the BRCA2 mutation. Olaparib was initiated with a resolution of the pleural effusion and a significant decrease in the size of the malignant lymphadenopathy and pulmonary lesions.  There are numerous reports of comprehensive molecular profiling improving access to therapy, most notably for lung cancer, as well as melanoma. However, this has not been widely utilized for breast cancer. However, in our case, NGS provided our patient with an effective therapy and should be considered for the future management of metastatic breast cancer.

Metastatic Hepatocellular Carcinoma Responsive to Pembrolizumab.

Hepatocellular carcinoma (HCC) is an aggressive liver tumor that occurs with chronic liver disease. Surgical resection is the mainstay of therapy for localized disease whereas therapeutic options for advanced disease are limited. The innovative blockade of immune checkpoints with targeted immunotherapies, such as monoclonal antibodies against programmed death receptor 1 (PD-1), have shown promise in the treatment of solid malignancies. The PD-1 inhibiting antibodies, nivolumab and pembrolizumab prolonged overall survival in randomized trials in metastatic melanoma and advanced non-small cell lung cancer. This is a report of a 75-year-old male patient with metastatic HCC who was initially treated with the standard of therapy sorafenib. After failure of sorafenib therapy, pembrolizumab was started. There was a dramatic response to pembrolizumab with decrease in tumor size and drop in alfa fetoprotein. To the best of our knowledge, this is the first case report of metastatic HCC responsive to pembrolizumab after failure of sorafenib.

Extensive Bone Marrow Necrosis and Osteolytic Lesions in a Case of Acute Myeloid Leukemia Transformed from Polycythemia Vera.

Acute myeloid leukemia (AML) is the most common leukemia in adults. In rare cases, bone marrow necrosis (BMN) and osteolytic lesions are presenting features of AML. The following case describes a patient with known polycythemia vera (PV) that presented with signs of multiple myeloma, including hypercalcemia, anemia, and lytic lesions of the thoracic spine and skull. Laboratory workup was not indicative of myeloma. A bone marrow biopsy was performed, which revealed extensive BMN and initial pathology was consistent with metastatic carcinoma. However, no immunohistochemical stains could be performed due to the extent of BMN; a repeat biopsy was therefore performed. Flow cytometry and CD45 staining were consistent with PV that had transformed to AML. Due to the patient's comorbidities, she was a poor candidate for stem cell transplant and did not wish to pursue chemotherapy. Ultimately, she pursued hospice care. Based on our literature review, both BMN and osteolytic lesions are rare manifestations of AML and have not been reported to occur simultaneously. These findings can lead to a diagnostic dilemma and suspicion of other malignancies. This case demonstrates that AML should remain in the differential diagnosis in those patients who present with BMN and osteolytic lesions.

Oxaliplatin-Induced Tonic-Clonic Seizures.

Oxaliplatin is a common chemotherapy drug used for colon and gastric cancers. Common side effects are peripheral neuropathy, hematological toxicity, and allergic reactions. A rare side effect is seizures which are usually associated with posterior reversible leukoencephalopathy syndrome (PRES). A 50-year-old male patient presented with severe abdominal pain. CT scan of the abdomen showed acute appendicitis. Appendectomy was done and pathology showed mixed adenoneuroendocrine carcinoma. Adjuvant chemotherapy was started with Folinic acid, Fluorouracil, and Oxaliplatin (FOLFOX). During the third cycle of FOLFOX, the patient developed tonic-clonic seizures. Laboratory workup was within normal limits. EEG and MRI of the brain showed no acute abnormality. The patient was rechallenged with FOLFOX but he had tonic-clonic seizures for the second time. His chemotherapy regimen was switched to Folinic acid, Fluorouracil, and Irinotecan (FOLFIRI). After 5 cycles of FOLFIRI, the patient did not develop any seizures, making Oxaliplatin the most likely culprit for his seizures. Oxaliplatin-induced seizures rarely occur in the absence of PRES. One case report has been described in the literature. We present a rare case of tonic-clonic seizures in a patient receiving Oxaliplatin in the absence of PRES.

Aberrant planar cell polarity induced by urinary tract obstruction.

Flow sensing by primary cilia of the epithelial cells is involved in cystogenesis in polycystic kidney disease. We investigate whether a similar mechanism applies to the pathogenesis of cyst-like tubular dilatation induced by ureteral obstruction in mice. Robust proliferation occurs in the obstructed tubules when urine flow is interrupted as well as in the repairing tubules when urine flow is reestablished after relief of the obstruction, suggesting a urine flow-independent mechanism of proliferation. In the urothelium, proliferation is only detected above the obstruction, although urine flow ceased both above and below the obstruction. Our results support mechanical strain- rather than flow-mediated proliferation in obstructive uropathy. To understand the mechanism of cell proliferation leading to increased tubular diameter in cyst-like tubular dilatation, we examine planar cell polarity (PCP), which is necessary for oriented cell division and maintenance of tubular diameter. In dilated tubules, the orientation of cell division is randomized, atypical PKC (aPKC) is mislocalized, and the pattern of the expression of a core PCP protein, Frizzled3 (Fz3), is altered. In addition, the level of Fz3 expression is increased. These results indicate that aberrant PCP may contribute to cyst-like tubular dilatation in obstructive uropathy. Interestingly, the orientation of cell division, localization of aPKC, and Fz3 expression return to normal when obstruction is relieved, which suggest a role of normal PCP signaling in tubular repair.