Computational Exploration of Naturally Occurring Flavonoids as TGF-ß Inhibitors in Breast Cancer: Insights from Docking and Molecular Dynamics Simulations and In-vitro Cytotoxicity Study.

Breast cancer is a global health concern, demanding innovative treatments. Targeting the Transforming Growth Factor-beta (TGF-ß) signaling pathway, pivotal in breast cancer, is a promising approach. TGF-ß inhibits proliferation via G1 phase cell cycle arrest, acting as a suppressor initially, but in later stages, it promotes progression by enhancing motility, invasiveness, and metastasis formation. This study explores naturally occurring flavonoids' interactions with TGF-ß. Using molecular docking against the protein's crystal structure (PDB Id: 1PY5), Gossypin showed the highest docking score and underwent molecular dynamics simulation, revealing complex flexibility and explaining how flavonoids impede TGF-ß signaling in breast cancer. ADMET predictions adhered to Lipinski's rule of Five. Insights into flavonoid-TGF-ß binding offer a novel angle for breast cancer treatment. Flavonoids having a good docking score like gossypin, morin, luteolin and taxifolin shown potent cytotoxic effect on breast cancer cell line, MCF-7. Understanding these interactions could inspire flavonoid-based therapies targeting TGF-ß to halt breast cancer growth. These findings pave the way for personalized, targeted breast cancer therapies, offering hope against this formidable disease.

3D extraoral morphometric changes after implant surgery: an exploratory pilot study using stereophotogrammetry.

OBJECTIVE: This pilot study aimed to evaluate, for the first time, the changes in facial tissues following the placement of a single dental implant. METHODS AND MATERIALS: Patients were scanned with a 3D facial scanner (3dMD) before implant surgery, immediately after surgery (T1), at 7 days post-operatively (T2), and at the impression stage (T3). Acquired images were processed using 3dMDVultus software program and volume differences and linear depth measurements were calculated to determine the morphometric changes over time. A total of 11 patients were included in the analyses. Descriptive statistics were employed to analyze the data. RESULTS: The volumetric changes and maximum depth differences indicated an initial increase, followed by a progressive decrease in tissue volume after implant placement in the area of the surgery. The volume change values ranged between 2.5 to 3.9 cc for T1, whereas for T2, the volume change decreased to a range of 0.8 to 1.8 cc. Maximum depth differences ranged between 2.06 to 2.80 mm in the soft tissues right after the implant surgery and reduced to around 2.01 mm to 0.55 mm in the impression stage. The amount of painkiller used was not related to the magnitude of linear depth measurements at any assessed time point. CONCLUSION: The results from this report documented that there is a longitudinal decrease in soft tissue volume and depth difference in extra-oral soft tissues in the region of implant placement after surgery to 6 weeks. The use of a facial scanner is a promising non-invasive method to monitor 3D morphometric changes after implant surgery.

Therapeutic monoclonal antibodies for COVID-19 management: an update.

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected more than 529 million people, and today the world is facing different mutant strains of the virus, leading to increased morbidity rates, fatality rates, and surfacing re-infections. Various therapies, such as prophylactic treatments, repurposed drug treatments, convalescent plasma, and polyclonal antibody therapy have been developed to help combat the coronavirus disease 2019 (COVID-19). AREA COVERED: This review article provides insights into the basic aspects of monoclonal antibodies (mAbs) for the therapy of COVID-19, as well as its advancement in terms of clinical trial and current approval status. EXPERT OPINION: Monoclonal antibodies represents the most effective and viable therapy and/or prophylaxis option against COVID-19, and have shown a reduction of the viral load, as well as lowering hospitalizations and death rates. In different countries, various mAbs are undergoing different phases of clinical trials, with a few of them having entered phases III and IV. Due to the soaring number of cases worldwide, the FDA has given emergency approval for the mAb combinations bamlanivimab with etesevimab and casirivimab with imdevimab.

Targeting histone demethylase LSD1 for treatment of deficits in autism mouse models.

Large-scale genetic studies have revealed that the most prominent genes disrupted in autism are chromatin regulators mediating histone methylation/demethylation, suggesting the central role of epigenetic dysfunction in this disorder. Here, we show that histone lysine 4 dimethylation (H3K4me2), a histone mark linked to gene activation, is significantly decreased in the prefrontal cortex (PFC) of autistic human patients and mutant mice with the deficiency of top-ranking autism risk factor Shank3 or Cul3. A brief treatment of the autism models with highly potent and selective inhibitors of the H3K4me2 demethylase LSD1 (KDM1A) leads to the robust rescue of core symptoms of autism, including social deficits and repetitive behaviors. Concomitantly, LSD1 inhibition restores NMDA receptor function in PFC and AMPA receptor-mediated currents in striatum of Shank3-deficient mice. Genome-wide RNAseq and ChIPseq reveal that treatment of Shank3-deficient mice with the LSD1 inhibitor restores the expression and H3K4me2 occupancy of downregulated genes enriched in synaptic signaling and developmental processes. The immediate early gene tightly linked to neuronal plasticity, Egr1, is on the top list of rescued genes. The diminished transcription of Egr1 is recapitulated in PFC of autistic human patients. Overexpression of Egr1 in PFC of Shank3-deficient mice ameliorates social preference deficits. These results have for the first time revealed an important role of H3K4me2 abnormality in ASD pathophysiology, and the therapeutic potential of targeting H3K4me2 demethylase LSD1 or the downstream molecule Egr1 for ASD.

Impact of Precision Medicine on Clinical Outcomes: A Single-Institution Retrospective Study.

PURPOSE: The strategy of precision medicine has been widely adopted in the practice of oncology, although the efficacy remains unclear. This study assesses clinical outcomes in patients with an actionable alteration found during FoundationOne CDx™ (F1CDx) testing and who received a targeted therapy based on the results. MATERIALS AND METHODS: This is a retrospective cohort study of patients with tumors that underwent F1CDx from September 2012 to July 2018. F1CDx provided actionable alterations for patients to select appropriate therapies. The primary objective was to estimate the objective response rate (ORR) at 3 months from the start of study treatment. The secondary objectives were to estimate progression-free survival (PFS) and overall survival (OS). RESULTS: One thousand patients underwent F1CDx testing. Six hundred fifty-two patients were identified as having actionable mutations. Thirty-eight patients (18 males and 20 females) received targeted therapy and were included in the study. The most common alterations were PD-1/PDL-1, high-TMB, P13K, and HER2/ERBB2. Patients received various treatments including nivolumab, pembrolizumab, trastuzumab, and everolimus. Eight (23.5%) and six (17.7%) patients achieved partial response (PR) and stable disease (SD), respectively; 20 (58.8%) had progression of disease (PD). The disease control rate was 41.2% (95% CI: 24.7% to 59.3%). The median PFS was 2.7 months (95% CI: 2.3 to 5.4 months), and median OS was 9.9 months (95% CI: 4.5 to 33.7 months). CONCLUSION: Our results demonstrate promising data in precision medicine in real community oncology practice. It warrants further large and prospective studies in patients with actionable alterations.

Predictors of inpatient mortality among children hospitalized for severe acute malnutrition: a systematic review and meta-analysis.

BACKGROUND: Malnutrition underlies 45% of under-5 deaths globally. Severe acute malnutrition (SAM) is the most serious form of undernutrition, characterized by wasting with or without edema. Mortality remains high (10%-40%) among children requiring hospitalization for complicated SAM. OBJECTIVES: We aimed to systematically document the factors independently associated with inpatient mortality in children with SAM. METHODS: Embase, Ovid MEDINE, the Cochrane Library, and clinicaltrials.gov were searched for articles published between January 2000 and January 2020, using a prespecified protocol. Eligible studies included children aged ≤59 mo hospitalized with SAM and used multivariable analysis to assess the baseline factors independently associated with inpatient mortality. Random-effects meta-analysis, stratified by the stated measure of effect, was used where >20% of studies included the same factor in analyses. RESULTS: Twenty-eight of 1432 studies fulfilled inclusion criteria: 19 studies included all children with SAM and 9 included specific subgroups of children with SAM. All 19 main studies were from 8 countries across Africa, with a median of 400 children/study. The mean inpatient mortality was 15.7% (95% CI: 10.4%, 21.0%) and HIV prevalence ranged from 2.1% to 51%. Nine factors were included in the meta-analysis, stratified by HR and OR. HIV infection (HR: 4.32; 95% CI: 2.31, 8.08), weight-for-height z score (WHZ) (OR: 0.44; 95% CI: 0.24, 0.80), diarrhea (HR: 2.84; 95% CI: 1.40, 5.75), pneumonia (HR: 1.89; 95% CI: 1.19, 3.02), presence of shock (HR: 3.67; 95% CI: 2.24, 6.03), and lack of appetite (HR: 2.16; 95% CI: 1.48, 3.16) were associated with increased mortality, whereas child age and sex were not. The association between edema and mortality was difficult to ascertain from the available studies. CONCLUSIONS: HIV infection, diarrhea, pneumonia, shock, lack of appetite, and lower WHZ are independent predictors of inpatient mortality in children with SAM. These factors may help to risk-stratify children being hospitalized with complicated SAM.This systematic review/meta-analysis protocol was registered at www.crd.york.ac.uk/prospero as CRD42019152267.

COVID-19 and Cancer Patients.

COVID-19 has now been declared a global pandemic with evolving incidence rates and fatalities. It is important to identify vulnerable populations who will be impacted most by this pandemic leading to higher mortality rates compared to the general healthy population. Although older patients and patients with co-morbidities fall into this vulnerable group, patients with hematologic and oncologic malignancies on active cytotoxic treatments are at even greater risk as they are both myelosuppressed and immunosuppressed. In addition to following the universal guidelines recommended by the Centers for Disease Control (CDC), it is important to also institute guidelines for cancer centers to help protect this vulnerable population. We review the current data, risks, and recommendations for COVID-19 in cancer patients.

Management of Pancreatic Cancer During COVID-19 Pandemic: To Treat or Not to Treat?

Pancreatic cancer is a very aggressive disease and survival remains dismal even with treatment. Currently, management of patients with pancreatic cancer has been complicated by the ongoing COVID-19 pandemic. Medical oncologists face the dilemma of whether to treat or to not treat these patients who are at high-risk of complications and even death from COVID-19. No current guidelines are available and our limited experience at this time makes it more difficult to manage these patients. Although we have general strategies available from experience in Italy, we need more treatment specific strategies to help mitigate risks of complications and toxicities from chemotherapy in order to protect our patients from COVID-19 as much as possible.

Treatment options in BRAF-mutant metastatic colorectal cancer.

B-type Raf kinase (BRAF) mutations occur in approximately 10% of patients with metastatic colorectal cancers (mCRC). Tumors harboring this mutation have a unique molecular profile and clinical phenotype. Response rate to systemic chemotherapy is poor and associated with shorter survival rate. Although BRAF inhibition dramatically changed treatment for melanoma patients, similar clinical responses were not observed in BRAF-mutant CRC, proposing a distinct mechanism of carcinogenesis. The aggressive biology of BRAF-mutated mCRC has underlined the importance of developing new therapeutic agents to improve outcomes in these patients. Despite numerous attempts, chemotherapy regimens are limited for this population. Reactivation of mitogen activated protein kinase pathway may explain the resistance to monotherapy, thus different combinations to target the pathway at different levels have been studied. This article will describe most suitable treatment options for CRC patients with BRAF mutation and discuss new emerging agents.

Extra-skeletal manifestations in mice affected by Clcn7-dependent autosomal dominant osteopetrosis type 2 clinical and therapeutic implications.

Autosomal dominant osteopetrosis type 2 (ADO2) is a high-density brittle bone disease characterized by bone pain, multiple fractures and skeletal-related events, including nerve compression syndrome and hematological failure. We demonstrated that in mice carrying the heterozygous Clcn7 G213R mutation, whose human mutant homolog CLCN7 G215R affects patients, the clinical impacts of ADO2 extend beyond the skeleton, affecting several other organs. The hallmark of the extra-skeletal alterations is a consistent perivascular fibrosis, associated with high numbers of macrophages and lymphoid infiltrates. Fragmented clinical information in a small cohort of patients confirms extra-skeletal alterations consistent with a systemic disease, in line with the observation that the CLCN7 gene is expressed in many organs. ADO2 mice also show anxiety and depression and their brains exhibit not only perivascular fibrosis but also ß-amyloid accumulation and astrogliosis, suggesting the involvement of the nervous system in the pathogenesis of the ADO2 extra-skeletal alterations. Extra-skeletal organs share a similar cellular pathology, confirmed also in vitro in bone marrow mononuclear cells and osteoclasts, characterized by an impairment of the exit pathway of the Clcn7 protein product, ClC7, through the Golgi, with consequent reduced ClC7 expression in late endosomes and lysosomes, associated with high vesicular pH and accumulation of autophagosome markers. Finally, an experimental siRNA therapy, previously proven to counteract the bone phenotype, also improves the extra-skeletal alterations. These results could have important clinical implications, supporting the notion that a systematic evaluation of ADO2 patients for extra-skeletal symptoms could help improve their diagnosis, clinical management, and therapeutic options.

Pharmacokinetics and pharmacodynamics of new drugs for pancreatic cancer.

Introduction: Pancreatic cancer (PC) remains a disease with a dismal prognosis. Despite accounting for only 3% of cancer diagnosis, 7% of all cancer deaths in the United States are from PC. This is explained by many being diagnosed with late-stage disease and the cancer's resistance to chemotherapy. Since 1996 there have only been two upfront regimens found to be superior to gemcitabine, FOLFIRINOX (5-fluorouracil/leucovorin and oxaliplatin) and gemcitabine plus nab-paclitaxel. Areas covered: Clinical pharmacology of newer agents that are either approved or being investigated in the management of PC. Knowledge of their pharmacokinetics, pharmacodynamics, and pharmacogenetics can be used to predict outcomes for specific patient populations. Drugs discussed include nanoliposomal irinotecan, pegvorhyaluronidase alfa, poly (ADP-ribose) polymerase enzyme inhibitors, larotrectinib, and napabucasin. Expert opinion: PC is a heterogeneous disease and outcomes are likely to improve as better predictive models of an individual's response to different therapies are developed. This may be best accomplished through phase 0 studies and the use of tumor organoid models grown from initial biopsies or resected tissue. The genetic and physical makeup of the tumor as well as the functional characterization in patient-derived organoids (PDOs), can help guide which agents may be most efficacious or toxic.

Monocytopenia in clozapine-induced agranulocytosis: insights into pathophysiology and treatment.

A 26-year-old man with history of schizophrenia was admitted for neutropaenia. He was started on clozapine 3 months prior to admission. As a result he had weekly monitoring of his blood counts and on day of admission was noted to have an absolute neutrophil count (ANC) of 450 cells/µL. He was admitted for clozapine-induced agranulocytosis. Clozapine was held and the patient was started on granulocyte colony-stimulating factor (G-CSF) filgrastim and received two doses without any signs of ANC recovery. On further review, it was noted that the absolute monocyte count (AMC) was also low and tracked with the trend of ANC. We then theorised that the impact of clozapine was on a haematopoietic precursor (colony-forming unit granulocyte-macrophage, CFU-GM) which gives rise to both monocytic and myeloid lineages. Therefore, sargramostim GM-CSF was started. After two doses, the ANC and AMC started trending up and by the third dose, both counts had fully recovered. He was discharged from the hospital and there are no plans to rechallenge with clozapine. Thus, we demonstrate a case of monocytopenia accompanying clozapine-induced agranulocytosis with successful use of GM-CSF. At least in this case, the target of the clozapine injury appears to be the CFU-GM, explaining the rapid and full response to GM-CSF after lack of response to G-CSF.

Why HALO 301 Failed and Implications for Treatment of Pancreatic Cancer.

Survival rates for pancreatic cancer (PC) remain dismal. Current standard of care treatment regimens provide transient clinical benefit but eventually chemoresistance develops leading to poor outcomes. PC is a relatively chemoresistant tumor and one of the explanations for this is attributed to desmoplasia that impedes drug delivery. Based on this, stromal modifying agent such as Pegvorhyaluronidase alfa (PEGPH20) was developed and investigated in phase I-III studies. Although phase I-II studies showed promising results in patients with high hyaluronic acid (HA) expressing tumors, the phase III HALO 301 study failed to miss it's primary endpoint and further development of PEHPH20 is halted. This failure implies that targeting desmoplasia alone is not sufficient and other intrinsic factors such as lack of significant neoantigens, low tumor mutational burden, and epithelial to mesenchymal transition may be at play. It is also important to consider that although the tumor stroma may be a physical barrier hampering drug delivery, it may also have protective effects in restraining tumor growth and progression. Further studies in molecular biology to better characterize the complex interaction between the microenvironment and cancer cells are warranted.

PARP Inhibitors in Pancreatic Cancer: From Phase I to Plenary Session.

Survival rates for pancreatic cancer remain dismal. Current standard of care treatment regimens provide transient clinical benefit but eventually chemoresistance develops. Tumors deficient in deoxyribonucleic acid (DNA) damage repair mechanisms such as BRCA mutants show better responses to platinum based agents, however, such tumors can utilize the poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) pathway as a salvage mechanism. Therefore, inhibition of PARP pathway could lead to tumor destruction and synthetic lethality in presence of BRCA mutation. Various PARP inhibitors have been approved for treatment of patients with germline or somatic BRCA mutant breast and ovarian cancer. This provides basis of using PARP inhibitors in patients with pancreatic cancer that harbor BRCA mutation. A recent phase III Pancreas Cancer Olaparib Ongoing (POLO) study showed impressive results with near doubling of progression free survival compared to placebo (7.4 vs 3.8 months). These results highlight the importance of germline testing for all patients with pancreatic cancer and inclusion of additional deficiencies in homologous recombination repair (ATM and PALB2) including BRCA variants of uncertain significance should be further explored.

RNA interference therapy for autosomal dominant osteopetrosis type 2. Towards the preclinical development.

Autosomal Dominant Osteopetrosis type 2 (ADO2) is a rare bone disease characterized by dense and brittle bones due to impairment of osteoclast bone resorption. Dominant negative mutations of the CLCN7 gene affect about 70% of ADO2 patients. ADO2 has no cure and our recent work established that it is suitable for gene silencing by a specific small interfering RNA that does not affect the normal mRNA, thus inducing a condition of pseudo-haplosufficiency and rescuing the bone phenotype. We performed a systematic study to test the likelihood that the therapy could progress towards clinical trials, treating Clcn7G213R/WT ADO2 mice with Clcn7G213R-specific siRNA and investigating the bone phenotype by µCT and histomorphometry, and safety, by histopathology and serology. We demonstrated that our Clcn7G213R siRNA is not only effective in pre-pubertal ADO2 male mice as we showed in our previous study, but also in adult and ageing mice, in males and females, by intraperitoneal and subcutaneous administration. Furthermore, the study also showed safety following prolonged chronic administration and allowed us to identify specific end-points to be potentially used in clinical trials. These results may pave the way towards regulatory toxicity studies, through which the therapy, that is patent-protected, can obtain approval from public health authorities for the transition to the Phase I/II clinical trials. The study also suggests that similar strategies could be applied to other autosomal dominant bone diseases, opening an avenue for a wider use of the RNA interference therapy in rare genetic disorders.