Hap2-Ino80-facilitated transcription promotes de novo establishment of CENP-A chromatin.

Centromeres are maintained epigenetically by the presence of CENP-A, an evolutionarily conserved histone H3 variant, which directs kinetochore assembly and hence centromere function. To identify factors that promote assembly of CENP-A chromatin, we affinity-selected solubilized fission yeast CENP-ACnp1 chromatin. All subunits of the Ino80 complex were enriched, including the auxiliary subunit Hap2. Chromatin association of Hap2 is Ies4-dependent. In addition to a role in maintenance of CENP-ACnp1 chromatin integrity at endogenous centromeres, Hap2 is required for de novo assembly of CENP-ACnp1 chromatin on naïve centromere DNA and promotes H3 turnover on centromere regions and other loci prone to CENP-ACnp1 deposition. Prior to CENP-ACnp1 chromatin assembly, Hap2 facilitates transcription from centromere DNA. These analyses suggest that Hap2-Ino80 destabilizes H3 nucleosomes on centromere DNA through transcription-coupled histone H3 turnover, driving the replacement of resident H3 nucleosomes with CENP-ACnp1 nucleosomes. These inherent properties define centromere DNA by directing a program that mediates CENP-ACnp1 assembly on appropriate sequences.

Transmission dynamics, complications and mitigation strategies of the current mpox outbreak: A comprehensive review with bibliometric study.

As the mankind counters the ongoing COVID-19 pandemic by the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), it simultaneously witnesses the emergence of mpox virus (MPXV) that signals at global spread and could potentially lead to another pandemic. Although MPXV has existed for more than 50 years now with most of the human cases being reported from the endemic West and Central African regions, the disease is recently being reported in non-endemic regions too that affect more than 50 countries. Controlling the spread of MPXV is important due to its potential danger of a global spread, causing severe morbidity and mortality. The article highlights the transmission dynamics, zoonosis potential, complication and mitigation strategies for MPXV infection, and concludes with suggested 'one health' approach for better management, control and prevention. Bibliometric analyses of the data extend the understanding and provide leads on the research trends, the global spread, and the need to revamp the critical research and healthcare interventions. Globally published mpox-related literature does not align well with endemic areas/regions of occurrence which should ideally have been the scenario. Such demographic and geographic gaps between the location of the research work and the endemic epicentres of the disease need to be bridged for greater and effective translation of the research outputs to pubic healthcare systems, it is suggested.

National trends in neoadjuvant chemotherapy utilization in patients with early-stage node-negative triple-negative breast cancer: the impact of the CREATE-X trial.

PURPOSE: Neoadjuvant chemotherapy (NAC) for triple-negative breast cancer (TNBC) allows for assessment of tumor pathological response and has survival implications. In 2017, the CREATE-X trial demonstrated survival benefit with adjuvant capecitabine in patients TNBC and residual disease after NAC. We aimed to assess national rates of NAC for cT1-2N0M0 TNBC before and after CREATE-X and examine factors associated with receiving NAC vs adjuvant chemotherapy (AC). METHODS: A retrospective cohort study of women with cT1-2N0M0 TNBC diagnosed from 2014 to 2019 in the National Cancer Database (NCDB) was performed. Variables were analyzed via ANOVA, Chi-squared, Fisher Exact tests, and a multivariate linear regression model was created. RESULTS: 55,633 women were included: 26.9% received NAC, 52.4% AC, and 20.7% received no chemotherapy (median ages 53, 59, and 71 years, p < 0.01). NAC utilization significantly increased over time: 19.5% in 2014-15 (n = 3,465 of 17,777), 27.1% in 2016-17 (n = 5,140 of 18,985), and 33.6% in 2018-19 (n = 6,337 of 18,871, p < 0.001). On multivariate analysis, increased NAC was associated with younger age (< 50), non-Hispanic white race/ethnicity, lack of comorbidities, cT2 tumors, care at an academic or integrated-network cancer program, and diagnosis post-2017 (p < 0.05 for all). Patients with government-provided insurance were less likely to receive NAC (p < 0.01). Women who traveled > 60 miles for treatment were more likely to receive NAC (p < 0.01). CONCLUSION: From 2014 to 2019, NAC utilization increased for patients with cT1-2N0M0 TNBC. Racial, socioeconomic, and access disparities were observed in who received NAC vs AC and warrants interventions to ensure equitable care.

Does Neoadjuvant Chemotherapy in Clinical T1-T2 N0 Triple-Negative Breast Cancer Increase the Extent of Axillary Surgery?

BACKGROUND: Current management strategies for early-stage triple-negative breast cancer (TNBC) include upfront surgery to determine pathologic stage to guide chemotherapy recommendations, or neoadjuvant chemotherapy (NAC) to de-escalate surgery, elucidate tumor response, and determine the role of adjuvant chemotherapy. However, patients who receive NAC with residual pathological nodal (pN) involvement require axillary lymph node dissection (ALND) as they are Z11/AMAROS ineligible. We aimed to evaluate the impact of NAC compared with upfront surgery on pN status and ALND rates in cT1-2N0 TNBC. METHODS: The National Cancer Database (NCDB) was queried for women with operable cT1-2N0 TNBC from 2014 to 2019. Demographic, clinicopathologic, and treatment data were collected. Multivariable linear regression analysis was performed to assess the odds of pN+ disease and undergoing ALND. RESULTS: Overall, 55,624 women were included: 26.9% (n = 14,942) underwent NAC and 73.1% (n = 40,682) underwent upfront surgery. The NAC cohort was younger (mean age 52.9 vs. 61.3 years; p < 0.001) with more cT2 tumors (71.6% vs. 31.0%; p < 0.001), and had lower ALND rates (4.3% vs. 5.5%; p < 0.001). The upfront surgery cohort was more likely to have one to three pathologically positive nodes (12.1% vs. 6.5%; odds ratio [OR] 2.37, 95% confidence interval (CI) 2.17-2.58; p < 0.001) but there was no difference in the likelihood of ALND (OR 1.1, 95% CI 0.99-1.24; p = 0.08). CONCLUSION: Patients who underwent upfront surgery were more likely to be pN+; however, ALND rates were similar between the two cohorts. Thus, the use of NAC does not result in a higher odds of ALND and the decision for NAC should be individualized and based on modern guidelines and systemic therapy benefits.

Lobular Neoplasia Diagnosed by MRI-Guided Breast Biopsy: Identifying Upgrade Rate to Malignancy and Outcomes of Clinical and Surgical Management.

OBJECTIVE: The aim of this study was to determine surgical and clinical outcomes of lobular neoplasia (LN) diagnosed by magnetic resonance imaging (MRI) biopsy, including upgrade to malignancy, and to assess for characteristics associated with upgrade. METHOD: A single-institution retrospective study, between 2013 and 2022, of patients with histopathological findings of LN via MRI-guided biopsy was performed using an institutional database and review of the electronic medical records. Decision for excision or surveillance was made by a multidisciplinary team per institutional practice. Patient demographics and imaging characteristics were summarized using descriptive analyses. Upgrade was defined as upgrade to cancer on surgical pathology for patients treated with excision or the development of cancer at the biopsy site during surveillance. The Wilcoxon rank-sum test and Fisher's exact test were used to compare features of the upgraded cohort with the remainder of the group. RESULTS: Ninety-four MRI biopsies diagnosing LN were included. Median age was 57 years (range 37-78 years). Forty-six lesions underwent excision while 48 lesions were surveilled. The upgrade rate was 7.4% (7/94). Upgrades in the excised cohort consisted of pleomorphic lobular carcinoma in situ (LCIS; n = 1), ductal carcinoma in situ (DCIS; n = 3) and invasive lobular carcinoma (ILC; n = 2), while one interval development of DCIS was observed at the site of biopsy in the surveillance cohort. No MRI or patient variables were associated with upgrade. CONCLUSIONS: In this contemporary cohort of MRI-detected LNs, the upgrade rate was low. Omission of surgery for MRI-detected LNs in carefully selected patients may be considered in a shared decision-making capacity between the patient and the treatment team. Larger cohorts are needed to determine factors predictive of upgrade risk.

Society of Surgical Oncology Breast Disease Site Working Group Statement on Contralateral Mastectomy: Indications, Outcomes, and Risks.

Rates of contralateral mastectomy (CM) among patients with unilateral breast cancer have been increasing in the United States. In this Society of Surgical Oncology position statement, we review the literature addressing the indications, risks, and benefits of CM since the society's 2017 statement. We held a virtual meeting to outline key topics and then conducted a literature search using PubMed to identify relevant articles. We reviewed the articles and made recommendations based on group consensus. Patients consider CM for many reasons, including concerns regarding the risk of contralateral breast cancer (CBC), desire for improved cosmesis and symmetry, and preferences to avoid ongoing screening, whereas surgeons primarily consider CBC risk when making a recommendation for CM. For patients with a high risk of CBC, CM reduces the risk of new breast cancer, however it is not known to convey an overall survival benefit. Studies evaluating patient satisfaction with CM and reconstruction have yielded mixed results. Imaging with mammography within 12 months before CM is recommended, but routine preoperative breast magnetic resonance imaging is not; there is also no evidence to support routine postmastectomy imaging surveillance. Because the likelihood of identifying an occult malignancy during CM is low, routine sentinel lymph node surgery is not recommended. Data on the rates of postoperative complications are conflicting, and such complications may not be directly related to CM. Adjuvant therapy delays due to complications have not been reported. Surgeons can reduce CM rates by encouraging shared decision making and informed discussions incorporating patient preferences.

Resuscitation With Vitamin C, Hydrocortisone, and Thiamin in Children With Septic Shock: A Multicenter Randomized Pilot Study.

OBJECTIVES: Adjunctive therapy with vitamin C, hydrocortisone, and thiamin has been evaluated in adults, but randomized controlled trial (RCT) data in children are lacking. We aimed to test the feasibility of vitamin C, hydrocortisone, and thiamin in PICU patients with septic shock; and to explore whether the intervention is associated with increased survival free of organ dysfunction. DESIGN: Open-label parallel, pilot RCT multicenter study. The primary endpoint was feasibility. Clinical endpoints included survival free of organ dysfunction censored at 28 days and nine secondary outcomes, shock reversal, and two proxy measures of intervention efficacy. SETTING: Six PICUs in Australia and New Zealand. PATIENTS: Children of age between 28 days and 18 years requiring vasoactive drugs for septic shock between August 2019 and March 2021. INTERVENTIONS: Patients were assigned 1:1 to receive 1 mg/kg hydrocortisone every 6 hours (q6h), 30 mg/kg ascorbic acid q6h, and 4 mg/kg thiamin every 12 hours (n = 27), or standard septic shock management (n = 33). MEASUREMENTS AND MAIN RESULTS: Sixty of 77 (78%) eligible patients consented with 91% of approached parents providing consent. The median time from randomization to intervention was 44 (interquartile range [IQR] 29-120) min. Seventy of seventy-seven (28%) patients had received IV steroids before randomization. Median survival alive and free of organ dysfunction was 20.0 (0.0-26.0) days in the intervention and 21.0 (0.0-25.0) days in the standard care group. Median PICU length of stay was 5.3 (2.5-11.3) days in the intervention group versus 6.9 (3.0-11.5) days in the control group. Shock reversal occurred at a median of 35.2 (14.6-101.2) hours in the intervention group versus 47.3 (22.4-106.8) hours in the standard care group (median difference -12 hr; 95% CI, -56.8 to 32.7 hr). CONCLUSIONS: In children requiring vasopressors for septic shock, a protocol comparing adjunctive treatment with high-dose vitamin C, hydrocortisone, and thiamin versus standard care was feasible. These findings assist in making modifications to the trial protocol to enable a better-designed larger RCT.

Breast Conservation Surgery and Mastectomy Have Similar Locoregional Recurrence After Neoadjuvant Chemotherapy: Results From 1462 Patients on the Prospective, Randomized I-SPY2 Trial.

Neoadjuvant chemotherapy (NAC) increases rates of successful breast-conserving surgery (BCS) in patients with breast cancer. However, some studies suggest that BCS after NAC may confer an increased risk of locoregional recurrence (LRR). We assessed LRR rates and locoregional recurrence-free survival (LRFS) in patients enrolled on I-SPY2 (NCT01042379), a prospective NAC trial for patients with clinical stage II to III, molecularly high-risk breast cancer. Cox proportional hazards models were used to evaluate associations between surgical procedure (BCS vs mastectomy) and LRFS adjusted for age, tumor receptor subtype, clinical T category, clinical nodal status, and residual cancer burden (RCB). In 1462 patients, surgical procedure was not associated with LRR or LRFS on either univariate or multivariate analysis. The unadjusted incidence of LRR was 5.4% after BCS and 7.0% after mastectomy, at a median follow-up time of 3.5 years. The strongest predictor of LRR was RCB class, with each increasing RCB class having a significantly higher hazard ratio for LRR compared with RCB 0 on multivariate analysis. Triple-negative receptor subtype was also associated with an increased risk of LRR (hazard ratio: 2.91, 95% CI: 1.8-4.6, P < 0.0001), regardless of the type of operation. In this large multi-institutional prospective trial of patients completing NAC, we found no increased risk of LRR or differences in LRFS after BCS compared with mastectomy. Tumor receptor subtype and extent of residual disease after NAC were significantly associated with recurrence. These data demonstrate that BCS can be an excellent surgical option after NAC for appropriately selected patients.

Lactation Education for Surgeons: American Society of Breast Surgeons (ASBrS) Survey Demonstrates Strong Member Interest in Expanded Training.

BACKGROUND: The availability and extent of breastfeeding-specific surgical training has not been previously described. We aimed to survey breast surgeons on their lactation education and desire for additional knowledge. METHODS: Members of the American Society of Breast Surgeons were invited via email to anonymously complete an electronic survey from 27 October 2021 to 23 January 2022. The survey content included demographic information, sources of lactation education, and desired topics and methods for further training. Descriptive statistics were used to analyze the data. RESULTS: A total of 2698 surveys were delivered and 542 (20.1%) completed. While nearly all respondents (99%) reported treating lactating patients at least once or twice per year, 78% reported that their training was inadequate. The most frequently cited sources of lactation information were peer-to-peer informal knowledge sharing (50%) and personal experience with breastfeeding (44%). Nearly all respondents (99%) agreed that formal lactation education would benefit breast surgeons. Specific topics of interest included management of patients with complications of lactation (48%), management of lactating patients with a new diagnosis of breast cancer (47%), and counseling patients with pregnancy-associated breast cancer who desire to breastfeed (46%). The most frequently recommended educational formats included presentation at a national conference (60%), evidence-based management guidelines (58%), webinar (55%), and workshop/course (47%). CONCLUSION: Breast surgeons self-report minimal formal training in the management of benign and malignant breast disease in lactating patients and strong desire for expanded education. Development of clinical practice guidelines and additional educational content for surgeons should be considered to meet the needs of this patient population.

To Dissect or Not to Dissect: Can We Predict the Presence of Four or More Axillary Lymph Node Metastases in Postmenopausal Women with Clinically Node-Negative Breast Cancer?

BACKGROUND: Axillary lymph node (ALN) involvement is important for prognosis and guidance of multidisciplinary treatment of breast cancer patients. This study sought to identify preoperative clinicopathologic factors predictive of four or more pathologically positive ALNs in patients with cN0 disease and to develop a predictive nomogram to inform therapy recommendations. METHODS: Using an institutional prospective database, the study identified postmenopausal women with cN0 invasive breast cancer undergoing upfront sentinel lymph node biopsy (SLNB) with or without completion ALND (cALND) between 1993 and 2007. Logistic regression analyses identified factors predictive of four or more positive nodes in the cN0 population and patients with one, two, or more SLNs. RESULTS: The study identified 2532 postmenopausal women, 615 (24.3%) of whom underwent cALND. In the univariate analysis, tumor size, lymphovascular (LVI), histology, estrogen receptor (ER)-positive status, and multifocality/multicentricity were predictive of four or more positive nodes (n = 63; p < 0.05), and all except ER status were significant in the multivariate analysis. Of the 2532 patients, 1263 (49.2%) had hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative disease, and 30 (2.4%) were found to have four or more positive nodes. Of the 130 patients with exactly one positive SLN who underwent cALND (n = 130, 5.4%), 7 had four or more positive nodes, with grade as the only predictive factor (p = 0.01). Of the 33 patients with two or more positive SLNs who underwent cALND, 9 (27.3%) had four or more positive nodes after cALND, but no factors were predictive in this subset. CONCLUSION: Postmenopausal women with early-stage cN0 HR-positive, HER2-negative breast cancer with a single positive SLN had a very low risk (5%) of having four or more positive nodes on final pathology. With such a low risk of N2 disease, limited staging with SLNB may be sufficient to guide therapy decisions for this subset of patients.

Changes in Surgical Management of the Axilla Over 11 Years - Report on More Than 1500 Breast Cancer Patients Treated with Neoadjuvant Chemotherapy on the Prospective I-SPY2 Trial.

BACKGROUND: Axillary surgery after neoadjuvant chemotherapy (NAC) is becoming less extensive. We evaluated the evolution of axillary surgery after NAC on the multi-institutional I-SPY2 prospective trial. METHODS: We examined annual rates of sentinel lymph node (SLN) surgery with resection of clipped node, if present), axillary lymph node dissection (ALND), and SLN and ALND in patients enrolled in I-SPY2 from January 1, 2011 to December 31, 2021 by clinical N status at diagnosis and pathologic N status at surgery. Cochran-Armitage trend tests were calculated to evaluate patterns over time. RESULTS: Of 1578 patients, 973 patients (61.7%) had SLN-only, 136 (8.6%) had SLN and ALND, and 469 (29.7%) had ALND-only. In the cN0 group, ALND-only decreased from 20% in 2011 to 6.25% in 2021 (p = 0.0078) and SLN-only increased from 70.0% to 87.5% (p = 0.0020). This was even more striking in patients with clinically node-positive (cN+) disease at diagnosis, where ALND-only decreased from 70.7% to 29.4% (p < 0.0001) and SLN-only significantly increased from 14.6% to 56.5% (p < 0.0001). This change was significant across subtypes (HR-/HER2-, HR+/HER2-, and HER2+). Among pathologically node-positive (pN+) patients after NAC (n = 525) ALND-only decreased from 69.0% to 39.2% (p < 0.0001) and SLN-only increased from 6.9% to 39.2% (p < 0.0001). CONCLUSIONS: Use of ALND after NAC has significantly decreased over the past decade. This is most pronounced in cN+ disease at diagnosis with an increase in the use of SLN surgery after NAC. Additionally, in pN+ disease after NAC, there has been a decrease in use of completion ALND, a practice pattern change that precedes results from clinical trials.

Cognitive Correlates of Visual and Minor Hallucinations in Parkinson's Disease.

INTRODUCTION: Psychosis is one of the incapacitating nonmotor symptoms of Parkinson's disease (PD). Although several risk factors that include older age, rapid eye movement sleep behavior disorder, depression, and cognitive dysfunction have been identified, the exact neural correlates remain elusive. As cognitive impairment has a close association with psychosis in PD, it is useful to know the spectrum of cognitive impairment in PD patients with psychosis (PD-P). METHODS: This cross-sectional study compared various cognitive parameters of PD-P (visual/minor hallucinations) and PD patients with no psychosis (PD-NP). A neuropsychological battery encapsulating several cognitive domains (executive, visuospatial, learning, and memory) was used for the cognitive assessment of 37 PD-P and 51 PD-NP patients who were matched for age, gender, education, and disease duration. RESULTS: The two groups were comparable in terms of disease severity and stage. Although the groups had a comparable mean score on Montreal cognitive assessment, the PD-P group performed poorly in tests focused on executive function (color trail test, forward digit span), verbal learning and memory (Rey auditory and verbal learning test), and visuospatial functions (complex figure test, corsi block tapping test). Those with complex visual hallucinations performed poorly in the color trial test (part A) compared to those with minor hallucinations. CONCLUSION: Psychosis is associated with a multidomain cognitive dysfunction in PD. All PD patients should undergo detailed cognitive assessment as cognitive dysfunction may be a marker of psychosis in the future. Additional longitudinal studies are warranted to obtain detailed insights into this issue.

Trends in Childhood Oncology Admissions to ICUs in Australia and New Zealand.

OBJECTIVES: There are few robust, national-level reports of contemporary trends in pediatric oncology admissions, resource use, and mortality. We aimed to describe national-level data on trends in intensive care admissions, interventions, and survival for children with cancer. DESIGN: Cohort study using a binational pediatric intensive care registry. SETTING: Australia and New Zealand. PATIENTS: Patients younger than 16 years, admitted to an ICU in Australia or New Zealand with an oncology diagnosis between January 1, 2003, and December 31, 2018. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We examined trends in oncology admissions, ICU interventions, and both crude and risk-adjusted patient-level mortality. Eight thousand four hundred ninety admissions were identified for 5,747 patients, accounting for 5.8% of PICU admissions. Absolute and population-indexed oncology admissions increased from 2003 to 2018, and median length of stay increased from 23.2 hours (interquartile range [IQR], 16.8-62 hr) to 38.8 hours (IQR, 20.9-81.1 hr) ( p < 0.001). Three hundred fifty-seven of 5,747 patients died (6.2%). There was a 45% reduction in risk-adjusted ICU mortality, which reduced from 3.3% (95% CI, 2.1-4.4) in 2003-2004 to 1.8% (95% CI, 1.1-2.5%) in 2017-2018 ( p trend = 0.02). The greatest reduction in mortality seen in hematological cancers and in nonelective admissions. Mechanical ventilation rates were unchanged from 2003 to 2018, while the use of high-flow nasal prong oxygen increased (incidence rate ratio, 2.43; 95% CI, 1.61-3.67 per 2 yr). CONCLUSIONS: In Australian and New Zealand PICUs, pediatric oncology admissions are increasing steadily and such admissions are staying longer, representing a considerable proportion of ICU activity. The mortality of children with cancer who are admitted to ICU is low and falling.

Evaluation of a Surgical Navigation System for Localization and Excision of Nonpalpable Lesions in Breast and Axillary Surgery.

Introduction: Elucent Medical has introduced a novel EnVisio™ Surgical Navigation system which uses SmartClips™ that generate a unique electromagnetic signal triangulated in 3 dimensions for real-time navigation. The purpose of this study was to evaluate the efficacy and feasibility of the EnVisio Surgical Navigation system in localizing and excising nonpalpable lesions in breast and axillary surgery. Methods: This pilot study prospectively examined patients undergoing breast and nodal localization using the EnVisio Surgical Navigation system. SmartClips were placed by designated radiologists using ultrasound (US) or mammographic (MMG) guidance. The technical evaluation focused on successful deployment and subsequent excision of all localized lesions including SmartClips and biopsy clips. Results: Eleven patients underwent localization using 27 SmartClips which included bracketed multifocal disease (n = 4) and clipped lymph node (n = 1). The bracketed cases were each localized with 2 SmartClips. Mammography and ultrasound were used (n = 8 and n = 19, respectively) to place the SmartClips. All 27 devices were successfully deployed within 5 mm of the targeted lesion or biopsy clip. All SmartClip devices were identified and retrieved intraoperatively. No patients required a second operation for margin excision. Conclusion: In a limited sample, the EnVisio Surgical Navigation system was a reliable technology for the localization of breast and axillary lesions planned for surgical excision. Further comparative studies are required to evaluate its efficacy in relation to the other existing localization modalities.

Febrile temperatures modulate the formation of immune complexes relevant for autoimmune diseases.

BACKGROUND: Autoimmune disorders encompass a diverse subset of diseases whose common symptoms include, among others, fever. Fever of unknown origins, once an infectious or tumor agent have been ruled out as possible causes, may originate with an autoimmune disease. OBJECTIVE: To determine the role of febrile temperatures on the stability of antigens pertinent to autoimmunity, and on the immune complexes they form with commercial therapeutic monoclonal antibodies. METHODS: Using molecular dynamics simulations, the binding between four antigens belonging to a set of autoimmune diseases and their individual monoclonal antibodies was investigated under different febrile temperatures. RESULTS: It was determined that at febrile temperatures, monoclonal antibodies used in the therapy of autoimmune diseases bind with higher binding free energy to pertinent antigens, once the autoimmune condition has been established and treatment is warranted. CONCLUSION: Performing molecular dynamics simulations at fever temperatures may be important for delineating the role antibodies may play in other diseases, including in cancers and infections.

Identifying SARS-CoV-2 Drugs Binding to the Spike Fatty Acid Binding Pocket Using In Silico Docking and Molecular Dynamics.

Drugs against novel targets are needed to treat COVID-19 patients, especially as SARS-CoV-2 is capable of rapid mutation. Structure-based de novo drug design and repurposing of drugs and natural products is a rational approach to discovering potentially effective therapies. These in silico simulations can quickly identify existing drugs with known safety profiles that can be repurposed for COVID-19 treatment. Here, we employ the newly identified spike protein free fatty acid binding pocket structure to identify repurposing candidates as potential SARS-CoV-2 therapies. Using a validated docking and molecular dynamics protocol effective at identifying repurposing candidates inhibiting other SARS-CoV-2 molecular targets, this study provides novel insights into the SARS-CoV-2 spike protein and its potential regulation by endogenous hormones and drugs. Some of the predicted repurposing candidates have already been demonstrated experimentally to inhibit SARS-CoV-2 activity, but most of the candidate drugs have yet to be tested for activity against the virus. We also elucidated a rationale for the effects of steroid and sex hormones and some vitamins on SARS-CoV-2 infection and COVID-19 recovery.

Clinical Outcomes Using Magnetic Seeds as a Non-wire, Non-radioactive Alternative for Localization of Non-palpable Breast Lesions.

BACKGROUND: Nonpalpable breast lesions require precise preoperative localization to facilitate negative margins with breast-conserving therapy. The traditional use of wires has several challenges including patient discomfort, wire migration, and coordination of schedules between radiology and the operating room. Radioactive seed localization overcomes some of these challenges, but radiation safety requirements have limited adoption of this technology. The authors examined their institutional experience with Magseed as an alternative technology for localization and compared outcomes with those of wire and radioactive seed localization. METHODS: An institutional review board (IRB)-approved retrospective study was performed to evaluate patients who underwent excisional biopsy or segmental mastectomy after wire-guided localization (WGL), radioactive seed localization (RSL), or Magseed localization (ML). The clinical and pathologic factors of the three groups were assessed with a negative margin rate as the primary outcome measure. RESULTS: Of the 1835 patients in the study, 825 underwent WGL, 449 underwent RSL, and 561 underwent ML. For the patients with either multiple lesions or a large lesion that required bracketing, multiple localization devices were placed in 31% of the WGL patients, 28% of the RSL patients, and 23% of the ML patients (p = 0.006). Negative margins were achieved in 91% of the WGL patients, 89% of the RSL patients, and 89% of the ML patients (p = 0.4). CONCLUSION: Localization of non-palpable breast lesions using Magseed is a safe and effective alternative to WGL and RSL that overcomes radiation safety limitations and increases radiology and surgery scheduling efficiency.

Targeting Apoptosis in Cancer.

PURPOSE OF REVIEW: Apoptosis is a major mechanism of cancer cell death. Thus, evasion of apoptosis results in therapy resistance. Here, we review apoptosis modulators in cancer and their recent developments, including MDM2 inhibitors and kinase inhibitors that can induce effective apoptosis. RECENT FINDINGS: Both extrinsic pathways (external stimuli through cell surface death receptor) and intrinsic pathways (mitochondrial-mediated regulation upon genotoxic stress) regulate the complex process of apoptosis through orchestration of various proteins such as members of the BCL-2 family. Dysregulation within these complex steps can result in evasion of apoptosis. However, via the combined evolution of medicinal chemistry and molecular biology, omics assays have led to innovative inducers of apoptosis and inhibitors of anti-apoptotic regulators. Many of these agents are now being tested in cancer patients in early-phase trials. We believe that despite a sluggish speed of development, apoptosis targeting holds promise as a relevant strategy in cancer therapeutics.

Potential COVID-19 Therapies from Computational Repurposing of Drugs and Natural Products against the SARS-CoV-2 Helicase.

Repurposing of existing drugs is a rapid way to find potential new treatments for SARS-CoV-2. Here, we applied a virtual screening approach using Autodock Vina and molecular dynamic simulation in tandem to screen and calculate binding energies of repurposed drugs against the SARS-CoV-2 helicase protein (non-structural protein nsp13). Amongst the top hits from our study were antivirals, antihistamines, and antipsychotics, plus a range of other drugs. Approximately 30% of our top 87 hits had published evidence indicating in vivo or in vitro SARS-CoV-2 activity. Top hits not previously reported to have SARS-CoV-2 activity included the antiviral agents, cabotegravir and RSV-604; the NK1 antagonist, aprepitant; the trypanocidal drug, aminoquinuride; the analgesic, antrafenine; the anticancer intercalator, epirubicin; the antihistamine, fexofenadine; and the anticoagulant, dicoumarol. These hits from our in silico SARS-CoV-2 helicase screen warrant further testing as potential COVID-19 treatments.

Sequential-Anaerobic and Sequential-Aerobic Bioleaching of Metals (Ni, Mo, Al and V) from Spent Petroleum Catalyst in Stirred Tank Batch Reactor: A Comparative Study.

Spent petroleum catalyst as a repository of several toxic metals is recommended for metal removal before safe disposal. To evaluate an effective biotechnological approach for metal removal, a comparative study between sequential-aerobic and sequential-anaerobic bioleaching processes was conducted for the removal of metals from crushed-acetone-pretreated spent petroleum catalyst. The SEM-EDX and XPS analysis confirmed the presence of Ni, Al, Mo and V in their oxidic and sulphidic forms in spent catalyst. The bioleaching experiments were performed in stirred tank batch reactors (2.5 L), temperature 30 °C, pH 1.4 and stirring speed 250 rpm for the period of 160 h. Sulfuric acid acted as lechant for both sequential-aerobic (Acidithiobacillus ferrooxidans oxidised sulfur to sulfuric acid aerobically) and sequential-anaerobic (Acidithiobacillus ferrooxidans oxidised sulphur to sulfuric acid coupled with the ferric reduction to ferrous anaerobically) bioleaching studies. The higher Ni and V extractions compared to Al and Mo for all the studies were due to increased solubility of Ni and V, and supported by XPS which showed marginal signs of Ni and V peaks in leach residues compared to feed spent catalyst. At the end (320 h), sequential-aerobic bioleaching was resulted to 99% Ni, 65% Al, 90% Mo and 99% V extraction quite more effective than sequential-anaerobic bioleaching (88% Ni, 28% Al, 33% Mo and 77% V) and sequential-control leaching (94% Ni, 20% Al, 40% Mo and 57% V). Although anaerobic bioleaching a possible approach, aerobic condition was found to be more suitable for sulfuric acid generation by A. ferrooxidans and high yield. So aerobic bioleaching is recommended to be favourable approach compared to anaerobic counterpart for future study and extrapolation. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12088-021-00978-8.