Antibody-Drug Conjugates: A Review of Approved Drugs and Their Clinical Level of Evidence.

Antibody-drug conjugates (ADCs) are an innovative family of agents assembled through linking cytotoxic drugs (payloads) covalently to monoclonal antibodies (mAbs) to be delivered to tumor tissue that express their particular antigen, with the theoretical advantage of an augmented therapeutic ratio. As of June 2023, eleven ADCs have been approved by the Food and Drug Administration (FDA) and are on the market. These drugs have been added to the therapeutic armamentarium of acute myeloblastic and lymphoblastic leukemias, various types of lymphoma, breast, gastric or gastroesophageal junction, lung, urothelial, cervical, and ovarian cancers. They have proven to deliver more potent and effective anti-tumor activities than standard practice in a wide variety of indications. In addition to targeting antigen-expressing tumor cells, bystander effects have been engineered to extend cytotoxic killing to low-antigen-expressing or negative tumor cells in the heterogenous tumor milieu. Inevitably, myelosuppression is a common side effect with most of the ADCs due to the effects of the cytotoxic payload. Also, other unique side effects are specific to the tissue antigen that is targeted for, such as the cardiac toxicity with Her-2 targeting ADCs, and the hemorrhagic side effects with the tissue factor (TF) targeting Tisotumab vedotin. Further exciting developments are centered in the strategies to improve the tolerability and efficacy of the ADCs to improve the therapeutic window; as well as the development of novel payloads including (1) peptide-drug conjugates (PDCs), with the peptide replacing the monoclonal antibody, rendering greater tumor penetration; (2) immune-stimulating antibody conjugates (ISACs), which upon conjugation of the antigen, cause an influx of pro-inflammatory cytokines to activate dendritic cells and harness an anti-tumor T-cell response; and (3) the use of radioactive isotopes as a payload to enhance cytotoxic activity.

Marine alkaloid rigidin analogues as potential selective inhibitors of SHP1, a new strategy for cancer immunotherapeutics.

SHP1 is a protein tyrosine phosphatase playing a central role in immunity, cell growth, development, and survival. The inhibition of SHP1 can help in better prognosis in various disorders like breast and ovarian cancer, melanoma, atherosclerosis, hypoxia, hypoactive immune response, and familial dysautonomia. The currently available inhibitors of SHP1 have the side effect of inhibiting the activity of SHP2, which shares >60% sequence similarity with SHP1 but has distinct biological functions. Thus, there is a need to search for novel specific inhibitors of SHP1. The current study uses a combination of virtual screening and molecular dynamic simulations, followed by PCA and MM-GBSA analysis, to screen about 35000 compounds; to predict that two rigidin analogues can potentially selectively inhibit SHP1 but not SHP2. Our studies demonstrate that these rigidin analogues are more potent at inhibiting SHP1 than the commercially available inhibitor NSC-87877. Further, cross-binding studies with SHP2 exhibited poor binding efficiency and lower stability of the complex, thus indicating a specificity of the rigidin analogues for SHP1, which is crucial in preventing side effects due to the diverse physiological functions of SHP2 in cellular signaling, proliferation, and hematopoiesis. Additionally, SHP1 is essential in mediating the inhibitory signaling in antitumor immune cells like NK and T cells. Hence, the rigidin analogues that inhibit SHP1 will potentiate the anti-tumor immune response by the release of inhibitory function of NK cells, thus driving NK activating response, in addition to their intrinsic anti-tumor function. Thus, SHP1 inhibition is a novel double-blade approach towards anti-cancer immunotherapeutics.Communicated by Ramaswamy H. Sarma.

Pneumothorax in Intubated Patients With COVID-19: A Case Series.

Pneumothorax is a rare complication among mechanically ventilated patients since low tidal volumes are used nowadays instead of traditional high tidal volumes, but the incidence is slightly higher in patients with high positive end-expiratory pressure (PEEP). Herein we describe a case series of nine patients who were on mechanical ventilation due to acute respiratory distress syndrome (ARDS) secondary to coronavirus disease 2019 (COVID-19) and developed pneumothorax in due course. A retrospective analysis was done on COVID-19 intubated patients from March 2020 to June 2020 in a community hospital in Central New Jersey, which was one of the early hit states in the United States at the beginning of the pandemic. Outcomes were studied. The demographics of patients like age, gender, and body mass index (BMI); risk factors like smoking, comorbidities especially chronic lung disease, and the treatment they received were compared. We compared the total number of days on the ventilator, the highest PEEP they received, and the ventilator day when pneumothorax developed. All the patients who developed pneumothorax had a chest tube inserted to treat it. The mortality was noted to be 100% indicating that pneumothorax is a life-threatening complication of COVID-19 and COVID-19 by itself is a risk factor for pneumothorax likely due to a change in lung mechanics. There is a need for large-scale studies to confirm that these outcomes are related to COVID-19.

Epicatechin analogues may hinder human parainfluenza virus infection by inhibition of hemagglutinin neuraminidase protein and prevention of cellular entry.

Human parainfluenza viruses (HPIVs) are ( -)ssRNA viruses belonging to Paramyoviridaie family. They are one of the leading causes of mortality in infants and young children and can cause ailments like croup, bronchitis, and pneumonia. Currently, no antiviral medications or vaccines are available to effectively treat parainfluenza. This necessitates the search for a novel and effective treatment. Computer-aided drug design (CADD) methodology can be utilized to discover target-based inhibitors with high accuracy in less time. A library of 45 phytocompounds with immunomodulatory properties was prepared. Thereafter, molecular docking studies were conducted to characterize the binding behavior of ligand in the binding pocket of HPIV3 HN protein. The physicochemical properties for screened compounds were computed, and the top hits from docking studies were further analyzed and validated using molecular dynamics simulation studies using the Desmond module of Schrodinger Suite 2021-1, followed by MM/GBSA analysis. The compounds CID:72276 (1) and CID:107905 (2) emerged as lead compounds of our in silico investigation. Further in vitro studies will be required to prove the efficacy of lead compounds as inhibitors and to determine the exact mechanism of their inhibition. Computational studies predict three natural flavonoids to inhibit the HN protein of HPIV3.

Exploring Data and Literature Currently Available on the COVID-19 Vaccines.

The COVID-19 pandemic has been labeled one of the most lethal pandemics in human history. As a result, there has been a high level of urgency throughout the world to establish successful vaccinations to subdue the effects of the virus and return to a level of normalcy. This study aims to investigate the different COVID-19 vaccines available both in the United States and across the globe. Through exploration of how the vaccines were developed, how they elicit immunity, their efficacy, and their safety profiles, this review has the goal of increasing the amount of knowledge regarding the vaccines available to combat SARS-CoV-2, while also providing an epidemiological and biostatistical approach to interpreting acquired data available on the vaccines.

Nanomaterials: An alternative source for biodegradation of toxic dyes.

Environment contamination is a colossal worriment across the world, owing to its detrimental and negative impact on health and ecological systems. Dyes are one of the synthetic organic chemicals that are utilised in a variety of fields, including textiles. As a result, throughout one's production and subsequently in fibre colouring, these are becoming frequent industry-contributed contaminants. Increasing globalisation of international market has presented a problem to textile sector in terms of consistency and production. Textile processors' primary concern, as the highly competitive environment and environmental standards grow more severe is about being mindful of the grade of goods and even non-toxicity of their production processes. There seems to be an immediate necessity to look for methods and technologies which are useful in removing dye colours. Even though each has benefits and weaknesses, many physical, chemical, and biological approaches were explored and used with the application being dependent on the effluent properties, technical feasibility, and cost. Several remediation technologies are already developed, but they seem to be ineffective at removing dyes completely. There is a fast growth of nanoparticles applications in the past few years which has opened up newer, innovating, highly efficient, and low-cost dyes remediation systems. Nanomaterials with large surface areas change surface characteristics and distinctive electron conducting capabilities which make them ideal candidate for the treatment of wastewater that contains dyes. In this review, we have highlighted not only the role of nanotechnology in dye remediation processes but also different types of nanomaterials that can be used for the remediation of dyes.

Structure-Based In Silico Investigation of Agonists for Proteins Involved in Breast Cancer.

Cancer is recognized as one of the main causes of mortality worldwide by the World Health Organization. The high cost of currently available cancer therapy and certain limitations of current treatment make it necessary to search for novel, cost-effective, and efficient methods of cancer treatment. Therefore, in the current investigation, sixty-two compounds from five medicinal plants (Tinospora cordifolia, Ocimum tenuiflorum, Podophyllum hexandrum, Andrographis paniculata, and Beta vulgaris) and two proteins that are associated with breast cancer, i.e., HER4/ErbB4 kinase and ERα were selected. Selected compounds were screened using Lipinski's rule, which resulted in eighteen molecules being ruled out. The remaining forty-four compounds were then taken forward for docking studies followed by molecular dynamics studies of the best screened complexes. Results showed that isocolumbin, isopropylideneandrographolide, and 14-acetylandrographolide were potential lead compounds against the selected breast cancer receptors. Furthermore, in vitro studies are required to confirm the efficacy of the lead compounds.

Multiple cutaneous and haemorrhagic brain metastases as the sentinel presentation of lung adenocarcinoma.

Skin is a relatively uncommon site of metastasis in lung cancer and is associated with a poor prognosis. Although, lung cancer does not uncommonly metastasise to the brain, haemorrhagic brain metastases are rarely reported. In this report, we present a dramatic presentation of a female smoker with a 3-week history of numerous cutaneous lesions over her body and two episodes of transient memory loss. Work-up demonstrated widely metastatic, poorly differentiated lung adenocarcinoma with haemorrhagic brain metastases. She proceeded with whole brain radiotherapy, but her performance status quickly declined afterwards; she succumbed to her malignancy within 6 weeks of presentation. This case presentation demonstrates that, for patients who present with cutaneous masses, especially those aged more than 60 years, and who have extensive smoking history, metastatic lung cancer should remain on the differential diagnosis. Also, the very poor prognosis of multiple metastases may influence medical and social decisions in the patient's treatment plan.

Thrombotic Thrombocytopenic Purpura: Revisiting a Miss and an Inevitable Consequence.

Thrombotic thrombocytopenic purpura (TTP) is typically characterized by the symptomatic pentad of fever, thrombocytopenia, microangiopathic hemolytic anemia, neurologic abnormalities, and renal failure. Atypical TTP is the diagnosis used to describe the subset of patients with TTP who present with symptoms that deviate from the classic pentad. We report a case an 86-year-old woman who presented to the emergency department complaining of chest pain for one day. She was reportedly on antibiotics for sinus infection. Physical examination revealed multiple bilateral superficial hematomas, predominantly on her extremities. On admission, her lab values were as follows: platelet count of 6,000/cubic millimeter, hemoglobin of 10.4 grams/deciliter, leukocyte count of 5100 cells/cubic millimeter, total bilirubin of 2.3 milligrams/deciliter, and troponin-I of 5.190 nanograms/milliliter. Peripheral blood smear was normal and did not reveal any schistocytes. The patient was admitted to the intensive care unit with a diagnosis of a non-ST-elevation myocardial infarction and a presumed diagnosis of immune thrombocytopenic purpura from antibiotic use. She was treated with intravenous solumedrol and a high-intensity statin. On the third day of her admission, the patient's mental functioning deteriorated and was intubated to protect her airway. A second peripheral smear revealed schistocytes, and subsequent laboratory studies supported the diagnosis of TTP. Plasma exchange therapy was planned. However, the patient succumbed to cardiac arrest before it could be initiated. The diagnosis was later confirmed with an ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) assay.  This case serves as an example of one of the many ways in which TTP can present, and emphasizes the importance of considering TTP as a differential diagnosis.

Assessment of head and neck position for optimal ultrasonographic visualisation of the internal jugular vein and its relation to the common carotid artery: A prospective observational study.

BACKGROUND AND AIMS: There is a wide variation in the anatomical relationship of the Internal Jugular Vein (IJV) to the Common Carotid Artery (CCA). This makes landmark based techniques of IJV cannulation and head rotation questionable and may lead to accidental arterial puncture. We conducted this study to determine the anatomical relation of the IJV to the CCA using (USG) in patients undergoing IJV cannulation for central venous access, and to analyse the effect of head rotation on this relationship. MATERIAL AND METHODS: A prospective observational study was conducted on 100 patients requiring central venous access, in the operation theatre or the intensive care unit. Anatomical relationship of the IJV to CCA at the level of the cricoid cartilage was analysed by noting the segment position (1-12) around the CCA using a high frequency linear USG probe on patients in neutral head position, on both sides and also with the head rotated to the contra lateral side by 15° and 45°. RESULTS: Antero-lateral segments 1 and 2 were the most common positions (50% on the right and 73% on the left side). Change in segment causing increase in overlap of IJV and CCA with 15° head rotation was seen in 44% subjects on the right and 39% on the left. Statistically, a higher number of subjects showed overlap with 45° rotation (99% on right and 97% on left, P < 0.05). CONCLUSION: There is a wide variation in anatomical location of the IJV in relation to the CCA as seen by USG. Excessive head rotation causes overlap of IJV over CCA which may cause inadvertent arterial puncture, even under USG guidance. Thus, it is preferable to cannulate the IJV in neutral or near neutral head and neck position.

Comparison of Efficacy of Epidural Ropivacaine versus Bupivacaine for Postoperative Pain Relief in Total Knee Replacement Surgeries.

BACKGROUND: Epidural analgesia has become the standard of care for knee replacement surgeries worldwide. Bupivacaine has been used successfully for many years. Epidural ropivacaine is now being used increasingly and seems to have benefits other than just pain relief, in terms of a better safety profile. AIM: To compare the efficacy of bupivacaine 0.125% (Group B) versus two concentrations of ropivacaine 0.1% (Group R1) and 0.2% (Group R2), in terms of pain scores, requirement of rescue analgesia, related adverse effects, and duration of postoperative (PO) hospital stay. MATERIALS AND METHODS: A retrospective study was conducted from the acute pain service data of patients who underwent joint replacement surgeries in one or both limbs, over a span of 6 months. Patients were allocated to and analyzed under one of the three groups based on the drug concentration used postoperatively by epidural infusion. Data retrieved were demographic data, daily average visual analog scale (VAS) pain scores, rescue analgesia given, adverse effects, and PO hospital stay days for all three groups. RESULTS: Demographic data were comparable between the three groups. Daily average VAS pain scores on days 1 and 2 were significantly higher in Group R1. Groups B and R2 were comparable. There was significantly more requirement of rescue analgesia in Group R1 on day 1. Day 2 showed no significant difference in rescue analgesic requirement in all three groups. Days of PO hospital stay were significantly higher in Group R1. Adverse effects such as hypotension and delayed motor block were higher in Group B. CONCLUSION: Ropivacaine 0.2% and bupivacaine 0.125% were equally efficacious in terms of VAS pain scores, rescue analgesic requirement, and duration of PO hospital stay, but ropivacaine had a better safety profile in terms of less hypotension and lesser motor block.

Analysis of functioning and efficiency of a code blue system in a tertiary care hospital.

BACKGROUND: "Code blue" (CB) is a popular hospital emergency code, which is used by hospitals to alert their emergency response team of any cardiorespiratory arrest. The factors affecting the outcomes of emergencies are related to both the patient and the nature of the event. The primary objective was to analyze the survival rate and factors associated with survival and also practical problems related to functioning of a CB system (CBS). MATERIALS AND METHODS: After the approval of hospital ethics committee, an analysis and audit was conducted of all patients on whom a CB had been called in our tertiary care hospital over 24 months. Data collected were demographic data, diagnosis, time of cardiac arrest and activation of CBS, time taken by CBS to reach the patient, presenting rhythm on arrival of CB team, details of cardiopulmonary resuscitation (CPR) such as duration and drugs given, and finally, events and outcomes. Chi-square test and logistic regression analysis were used to analyze the data. RESULTS: A total of 720 CB calls were initiated during the period. After excluding 24 patients, 694 calls were studied and analyzed. Six hundred and twenty were true calls and 74 were falls calls. Of the 620, 422 were cardiac arrests and 198 were medical emergencies. Overall survival was 26%. Survival in patients with cardiac arrests was 11.13%. Factors such as age, presenting rhythm, and duration of CPR were found to have a significant effect on survival. Problems encountered were personnel and equipment related. CONCLUSION: A CBS is effective in improving the resuscitation efforts and survival rates after inhospital cardiac arrests. Age, presenting rhythm at the time of arrest, and duration of CPR have significant effect on survival of the patient after a cardiac arrest. Technical and staff-related problems need to be considered and improved upon.

Perioperative sildenafil therapy for children with ventricular septal defects and associated pulmonary hypertension undergoing corrective surgery: A randomised clinical trial.

BACKGROUND AND AIMS: Sildenafil is known to reduce pulmonary artery pressure but its role in the perioperative period has not been well studied. We aimed to evaluate the efficacy of sildenafil in controlling post-operative pulmonary hypertension in children with pulmonary hypertension undergoing surgeries for correction of ventricular septal defect. METHODS: The patients were divided randomly into two groups of thirty each. Group 1 (placebo) received pre-operative placebo and post-operative sildenafil (0.5mg/kg every 6 hrs) while Group 2 (sildenafil) received pre- and post-operative sildenafil (0.5mg/kg every 6 hrs). RESULTS: In the Group 1, systolic pulmonary artery pressure reduced from 81.63 (±12.1) mmHg preoperatively to 79.26 (±11.29) mmHg pre-cardiopulmonary bypass (CPB) and 56.76 (±11) mmHg (with 10 minutes post-CPB), whereas in Group 2, it reduced from 83.3 (±12.1) before surgery to 68.9 (±11.3) mmHg pre-CPB and after CPB, to 42.2 (±7.6) mmHg (P = 0.001). The mean pulmonary artery pressure decreased from 60.63 (±10.5) mmHg to 42.13 (±8.3) mmHg in the Group 1 whereas it reduced from 54.36 (±10) mmHg to 31.36 (±6.5) mmHg in Group 2 (P = 0.001). The reductions in pulmonary artery/aortic ratio and Intensive Care Unit stay were statistically significant No adverse effects were recorded. CONCLUSION: The use of perioperative sildenafil has a statistically significant reduction in the mean pulmonary artery pressure without any adverse effects.

Comparison of laryngeal tube suction II and proseal LMA™ in pediatric patients, undergoing elective surgery.

BACKGROUND: Supraglottic airway devices now have an established place in pediatric anesthesia practice. The laryngeal tube suction (LTS) II, a recent revision of the LTS, has very few studies evaluating its use in pediatric patients. The aim of this study was to compare insertion and ventilation profiles of the LTS-II size 2 and the ProSeal™ Laryngeal Mask Airway (PLMA) size 2 in pediatric patients undergoing elective surgeries. MATERIALS AND METHODS: A randomized prospective study was conducted in 100 children aged 2-5 years between 12 and 25 kg weight, of the American Society of Anesthesiologists physical status I and II scheduled for routine elective surgeries of <90 min duration. They were randomly divided into two groups of 50 each, depending on the device inserted, and a standard protocol for anesthesia was followed. Outcome measures were studied in terms of ease and time of insertion, oxygen saturation (SpO2), oropharyngeal seal pressure (OSP), and ventilation failures. RESULTS: Both groups were well matched in terms of age, weight, and type of surgery. The success rate for the first attempt was 90% for both the LTS-II group and PLMA group. Insertion was found to be easy in the majority of cases in both groups, and there was no statistical difference in blood pressure, heart rate, or SpO2 on insertion. However, the OSP was significantly more in LTS-II and PLMA (P < 0.001). There were no clinically important complications in the postoperative period. CONCLUSIONS: Pediatric size 2 LTS-II is easy to insert and provides higher OSP compared with same size PLMA in anesthetized and paralyzed children undergoing elective surgery. It is a safe alternative to PLMA in short duration elective surgeries and may be a better device as it provides for higher OSPs.