Targeting LxCxE cleft pocket of retinoblastoma protein in immunosuppressive macrophages inhibits ovarian cancer progression.

Ovarian cancer remains a major health threat with limited treatment options available. It is characterized by immunosuppressive tumor microenvironment (TME) maintained by tumor-associated macrophages (TAMs) hindering anti-tumor responses and immunotherapy efficacy. Here we show that targeting retinoblastoma protein (Rb) by disruption of its LxCxE cleft pocket causes preferential cell death in Rbhigh M2 polarized or M2-like Rbhigh immunosuppressive TAMs by induction of ER stress, p53 and mitochondria-related cell death pathways.

The Natural Stilbenoid (-)-Hopeaphenol Inhibits HIV Transcription by Targeting Both PKC and NF-κB Signaling and Cyclin-Dependent Kinase 9.

Despite effective combination antiretroviral therapy (cART), people living with HIV (PLWH) continue to harbor replication-competent and transcriptionally active virus in infected cells, which in turn can lead to ongoing viral antigen production, chronic inflammation, and increased risk of age-related comorbidities. To identify new agents that may inhibit postintegration HIV beyond cART, we screened a library of 512 pure compounds derived from natural products and identified (-)-hopeaphenol as an inhibitor of HIV postintegration transcription at low to submicromolar concentrations without cytotoxicity. Using a combination of global RNA sequencing, plasmid-based reporter assays, and enzyme activity studies, we document that hopeaphenol inhibits protein kinase C (PKC)- and downstream NF-κB-dependent HIV transcription as well as a subset of PKC-dependent T-cell activation markers, including interleukin-2 (IL-2) cytokine and CD25 and HLA-DRB1 RNA production.

Human galectin-9 promotes the expansion of HIV reservoirs in vivo in humanized mice.

Objective: The human endogenous protein galectin-9 (Gal-9) reactivates latently HIV-infected cells in vitro and ex vivo , which may allow for immune-mediated clearance of these cells. However, Gal-9 also activates several immune cells, which could negatively affect HIV persistence by promoting chronic activation/exhaustion. This potential 'double-edged sword' effect of Gal-9 raises the question of the overall impact of Gal-9 on HIV persistence in vivo .

A Rapid Nucleic Acid Amplification Test-Based, Conditional Release-to-Work Policy for Health Care Personnel With Symptoms Consistent With COVID-19.

Objective: Most health care personnel (HCP) reporting symptoms consistent with COVID-19 illness are assessed by high-accuracy SARS-CoV-2 assays performed in clinical laboratories, but the results of such assays typically are not available until the following day.

Methods: This is an observational study over 16 weeks of a rapid nucleic acid amplification test (NAAT) performed at point of contact. The benchmark for comparison was a simultaneously obtained specimen assayed by a routine NAAT assay performed in a clinical laboratory.

BCL6 BTB-specific inhibitor reversely represses T-cell activation, Tfh cells differentiation, and germinal center reaction in vivo.

Inhibition of the BCL6 BTB domain results in killing Diffuse Large B-cell Lymphoma (DLBL) cells, reducing the T-cell dependent germinal center (GC) reaction in mice, and reversing GC hyperplasia in nonhuman primates. The available BCL6 BTB-specific inhibitors are poorly water soluble, thus, limiting their absorption in vivo and our understanding of therapeutic strategy targeting GC. We synthesized a prodrug (AP-4-287) from a potent BCL6 BTB inhibitor (FX1) with improved aqueous solubility and pharmacokinetics (PK) in mice.

Incidence and Characteristics of Delayed Injection Site Reaction to the mRNA-1273 Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Vaccine (Moderna) in a Cohort of Hospital Employees.

Background: mRNA SARS-CoV-2 vaccines are administered to 2 million individuals per day in the United States under US Food and Drug Administration emergency use authorization.

Methods: Observational cohort study of hospital employees who received their first SARS-CoV-2 mRNA vaccination between 14 December 2020 and 8 January 2021, including employees who reported onset of an injection site reaction ≥48 hours after administration of their first or second dose to an employee hotline.

Results: Thirteen female employees who received the mRNA-1273 vaccine (Moderna) during the first 3 weeks of the SARS-CoV-2 vaccine rollout at San Francisco General Hospital reported a pruritic rash at the injection site appearing 3 -9 days after receipt of their initial dose.

Test and vaccinate or remove: Methodology and preliminary results from a badger intervention research project.

Background: In the British Isles, it is generally accepted that the Eurasian badger (Meles meles) plays a role in the maintenance of bovine tuberculosis (bTB) in cattle. Non-selective culling is the main intervention method deployed in controlling bTB in badgers along with smaller scale Bacillus Calmette-Guérin (BCG) vaccination areas. This paper describes the use of selective badger culling combined with vaccination in a research intervention trial.

Flavonoid-based inhibition of cyclin-dependent kinase 9 without concomitant inhibition of histone deacetylases durably reinforces HIV latency.

While combination antiretroviral therapy (cART) durably suppresses HIV replication, virus persists in CD4 T-cells that harbor latent but spontaneously inducible and replication-competent provirus. One strategy to inactivate these viral reservoirs involves the use of agents that continue to reinforce HIV latency even after their withdrawal. To identify new chemical leads with such properties, we investigated a series of naturally-occurring flavones (chrysin, apigenin, luteolin, and luteolin-7-glucoside (L7G)) and functionally-related cyclin dependent kinase 9 (CDK9) inhibitors (flavopiridol and atuveciclib) which are reported or presumed to suppress HIV replication in vitro.

Stem cells of the lower limb: their role and potential in management of critical limb ischemia.

Peripheral arterial occlusive disease (PAOD) contributes to decreased exercise tolerance, poor balance, impaired proprioception, muscle atrophy and weakness, with advanced cases resulting in critical limb ischemia (CLI) where the viability of the limb is threatened. Patients with a diagnosis of CLI have a poor life expectancy due to concomitant cardio and cerebrovascular diseases. The current treatment options to avoid major amputation by re-establishing a blood supply to the limb generally have poor outcomes.

Duodenal rupture secondary to blunt trauma from a football.

Duodenal rupture secondary to blunt trauma is a relatively uncommon event and is usually a result of a road traffic accident. As the duodenum is a retroperitoneal organ, delays in diagnosis can occur, as the patient may present with vague abdominal symptoms and other non-specific signs. Computed tomographic scanning is therefore a useful tool in the diagnosis of this condition.

The emerging harm of antioxidants in carcinogenesis.

Early epidemiologic studies have hinted at an anticancer role for multiple antioxidant compounds that are present in fresh produce. These substances target reactive oxygen and nitrogen species and potentially reduce oxidative damage to DNA that results in mutagenic change and potentially the initiation of cancer, disease and aging. It is tempting to believe that these compounds, through their in vitro actions as observed in cancer cell lines and certain animal experiments, may have the same anticarcinogenic role in humans.

Mechanisms of reducing postoperative pain, nausea and vomiting: a systematic review of current techniques.

Background: Multimodal recovery programmes decrease hospital stay. The objective of this systematic review was to assess how single-modality evidence-based care principles, regarding postoperative analgesia and postoperative nausea and vomiting (PONV) prophylaxis, combine to achieve this.

Methods: A systematic review of randomised controlled trials was performed.

T-tube duodenocholangiostomy for the management of duodenal fistulae.

Background: The tube decompression of the duodenum through an additional point of access of the duodenal wall or occasionally via the leak site decreases morbidity and mortality in patients with duodenal fistula. The objective of this paper is to present the detailed technique and clinical benefits of simplified duodenal and biliary decompression achieved by transampullary insertion of a T-tube with one-step duodenal closure for the prevention and/or treatment of duodenal leak.

Methods: The duodenocholangiostomy using T-tube with laterally perforated long duodenal limb was performed preventively in 4 patients and as a secondary procedure for septic duodenal leak in another selected 12.

Pancreas sparing duodenectomy as an emergency procedure.

Background: The operative techniques to close extensive wounds to the duodenum are well described. However, postoperative morbidity is common and includes suture line leak and the formation of fistulae. The aim of this case series is to present pancreas sparing duodenectomy as a safe and viable alternative procedure in the emergency milieu.