Oncogenes and tumor suppressor genes: functions and roles in cancers.

Cancer, being the most formidable ailment, has had a profound impact on the human health. The disease is primarily associated with genetic mutations that impact oncogenes and tumor suppressor genes (TSGs). Recently, growing evidence have shown that X-linked TSGs have specific role in cancer progression and metastasis as well. Interestingly, our genome harbors around substantial portion of genes that function as tumor suppressors, and the X chromosome alone harbors a considerable number of TSGs. The scenario becomes even more compelling as X-linked TSGs are adaptive to key epigenetic processes such as X chromosome inactivation. Therefore, delineating the new paradigm related to X-linked TSGs, for instance, their crosstalk with autosome and involvement in cancer initiation, progression, and metastasis becomes utmost importance. Considering this, herein, we present a comprehensive discussion of X-linked TSG dysregulation in various cancers as a consequence of genetic variations and epigenetic alterations. In addition, the dynamic role of X-linked TSGs in sex chromosome-autosome crosstalk in cancer genome remodeling is being explored thoroughly. Besides, the functional roles of ncRNAs, role of X-linked TSG in immunomodulation and in gender-based cancer disparities has also been highlighted. Overall, the focal idea of the present article is to recapitulate the findings on X-linked TSG regulation in the cancer landscape and to redefine their role toward improving cancer treatment strategies.

Initial Experience With Robotic Liver Resection in the United States.

BACKGROUND: This study's aim was to show the feasibility and safety of robotic liver resection (RLR) even without extensive experience in major laparoscopic liver resection (LLR). METHODS: A single center, retrospective analysis was performed for consecutive liver resections for solid liver tumors from 2014 to 2022. RESULTS: The analysis included 226 liver resections, comprising 127 (56.2%) open surgeries, 28 (12.4%) LLR, and 71 (31.4%) RLR. The rate of RLR increased and that of LLR decreased over time. In a comparison between propensity score matching-selected open liver resection and RLR (41:41), RLR had significantly less blood loss (384 ± 413 vs 649 ± 646 mL, P = .030) and shorter hospital stay (4.4 ± 3.0 vs 6.4 ± 3.7 days, P = .010), as well as comparable operative time (289 ± 123 vs 290 ± 132 mins, P = .954). A comparison between LLR and RLR showed comparable perioperative outcomes, even with more surgeries with higher difficulty score included in RLR (5.2 ± 2.7 vs 4.3 ± 2.5, P = .147). The analysis of the learning curve in RLR demonstrated that blood loss, conversion rate, and complication rate consistently improved over time, with the case number required to achieve the learning curve appearing to be 60 cases. CONCLUSIONS: The findings suggest that RLR is a feasible, safe, and acceptable platform for liver resection, and that the safe implementation and dissemination of RLR can be achieved without solid experience of LLR.

Robotic management of huge hepatic angiomyolipoma: A case report and literature review.

Hepatic angiomyolipoma (HAML) is a rare, benign mesenchymal liver tumor encountered in Asia, primarily in females, and can be found within the right hepatic lobe, but also in other areas of the liver. Immunohistochemically, HAMLs are characteristically positive for human melanoma black-45 antigen (HMB-45) and can histochemically vary in the composition of angiomatous, lipomatous, and myomatous tissue, together with the presence of epithelioid cells. In this case report, we discuss a previously healthy patient presenting with bloating and previously documented concern of liver lesions, found to have HAML confirmed by surgical pathology. Surgery was decided, as HAMLs greater than 10 cm are at risk of rupture. This is one of the first documented cases of HAML resected through robot-assisted bisegmentectomy and cholecystectomy, and therefore, intraoperative images have been included to assist in the planning of future robotic cases.

The linked nail/plate construct for the management of distal femur fractures in the elderly.

BACKGROUND: Distal femoral fractures represent a challenging injury, with many different factors such as the method of fixation, complexity of fracture pattern, and patient co-morbidities affecting the outcome. Lots of surgical treatment options have been described, but recently double construct fixation, using a nail/plate combination, has received lots of attention, a technique that leads to faster weight-bearing, low risk of metalwork failure, and non-union. The purpose of this study was to investigate the effectiveness of the linked nail/plate construct in the management of complex distal femur fractures and to investigate if the above technique leads to faster recovery and earlier radiographic union. MATERIALS AND METHODS: In total 15 cases were included in the study, that underwent a combined nail/plate construct for a distal femur fracture between January 2021 and December 2022. Only cases with a linked nail/plate construct were included, with a minimum follow-up of 1 year. Open femur fractures, single implant fixation cases, and revision procedures were excluded. RESULTS: In this cohort study, 11 cases were periprosthetic distal femur features, and 4 cases were distal femur fractures around a native knee joint. The mean age group was 74 years, 86.6% of the patients had a BMI > 25 and the mean time to fracture union was 24 weeks (range from 20 to 26 weeks). All cases healed uneventfully and the complication rate was 6.6%, including 1 case of superficial infection which resolved completely with oral antibiotics. CONCLUSION: The increasing age population, the complexity of distal femoral fractures along with the increasing physiological demands of the elderly population, drive the need for double fixation constructs that allow early mobilization and enhance fracture stability. In our study, the linked nail/plate construct seems to provide adequate stability and excellent union rates (100%) with no associated increased risk of complications.

Bicyclic Pyrrolidine Inhibitors of Toxoplasma gondii Phenylalanine t-RNA Synthetase with Antiparasitic Potency In Vitro and Brain Exposure.

Previous studies have shown that bicyclic azetidines are potent and selective inhibitors of apicomplexan phenylalanine tRNA synthetase (PheRS), leading to parasite growth inhibition in vitro and in vivo, including in models of Toxoplasma infection. Despite these useful properties, additional optimization is required for the development of efficacious treatments of toxoplasmosis from this inhibitor series, in particular, to achieve optimal exposure in the brain. Here, we describe a series of PheRS inhibitors built on a new bicyclic pyrrolidine core scaffold designed to retain the exit-vector geometry of the isomeric bicyclic azetidine core scaffold while offering avenues to sample diverse chemical space. Relative to the parent series, bicyclic pyrrolidines retain reasonable potency and target selectivity for parasite PheRS vs host. Further structure-activity relationship studies revealed that the introduction of aliphatic groups improved potency and ADME and PK properties, including brain exposure. The identification of this new scaffold provides potential opportunities to extend the analogue series to further improve selectivity and potency and ultimately deliver a novel, efficacious treatment of toxoplasmosis.

Utility of scores to predict alcohol use after liver transplant (lt): take them with a grain of salt.

BACKGROUND AIMS: The Sustained Alcohol use post-Liver Transplant (SALT) and the High-Risk Alcohol Relapse (HRAR) scores were developed to predict return to alcohol use after liver transplant (LT) for alcohol associated liver disease (ALD). METHODS: A retrospective analysis of deceased donor LT 10/2018 to 4/2022 was performed. All patients (pts) underwent careful pre-LT psychosocial evaluation. Data on alcohol use, substance abuse, prior rehabilitation, and legal issues were collected. Post-LT, all were encouraged to participate in rehabilitation programs and underwent interval phosphatidylethanol (PeTH) testing. Pts with ALD were stratified by < or > 6 month sobriety prior to listing. Those with <6 month were further stratified as acute alcoholic hepatitis (AH) by NIAAA criteria and non-AH. The primary outcome was utility of the SALT (<5 vs. ≥5) and HRAR (<3 vs. ≥3) scores to predict return to alcohol use (+PeTH) within 1 year after LT. RESULTS: Of the 365 LT, 86 had > 6 month sobriety and 85 had <6 month sobriety; 41 with AH and 44 non-AH. In those with AH, the mean time of abstinence to LT was 58 days, and 71% failed prior rehabilitation. Following LT, return to drinking was similar in the AH (24%) compared to <6M non-AH (15%) and >6M ALD (22%). Only 4% had returned to heavy drinking. The accuracy of both the SALT and HRAR scores to predict return to alcohol was low (accuracy 61-63%) with poor sensitivity (46% and 37%), specificity (67-68%), positive predictive value (22-26%) with moderate negative predictive value (NPV) (81-83%), respectively with higher NPVs (95%) in predicting return to heavy drinking. CONCLUSIONS: Both SALT and HRAR scores had good NPV in identifying patients at low risk for recidivism.

Discovering single cannabidiol or synergistic antitumor effects of cannabidiol and cytokine-induced killer cells on non-small cell lung cancer cells.

Introduction: A multitude of findings from cell cultures and animal studies are available to support the anti-cancer properties of cannabidiol (CBD). Since CBD acts on multiple molecular targets, its clinical adaptation, especially in combination with cancer immunotherapy regimen remains a serious concern. Methods: Considering this, we extensively studied the effect of CBD on the cytokine-induced killer (CIK) cell immunotherapy approach using multiple non-small cell lung cancer (NSCLC) cells harboring diverse genotypes. Results: Our analysis showed that, a) The Transient Receptor Potential Cation Channel Subfamily V Member 2 (TRPV2) channel was intracellularly expressed both in NSCLC cells and CIK cells. b) A synergistic effect of CIK combined with CBD, resulted in a significant increase in tumor lysis and Interferon gamma (IFN-g) production. c) CBD had a preference to elevate the CD25+CD69+ population and the CD62L_CD45RA+terminal effector memory (EMRA) population in NKT-CIK cells, suggesting early-stage activation and effector memory differentiation in CD3+CD56+ CIK cells. Of interest, we observed that CBD enhanced the calcium influx, which was mediated by the TRPV2 channel and elevated phosphor-Extracellular signal-Regulated Kinase (p-ERK) expression directly in CIK cells, whereas ERK selective inhibitor FR180204 inhibited the increasing cytotoxic CIK ability induced by CBD. Further examinations revealed that CBD induced DNA double-strand breaks via upregulation of histone H2AX phosphorylation in NSCLC cells and the migration and invasion ability of NSCLC cells suppressed by CBD were rescued using the TRPV2 antagonist (Tranilast) in the absence of CIK cells. We further investigated the epigenetic effects of this synergy and found that adding CBD to CIK cells decreased the Long Interspersed Nuclear Element-1 (LINE-1) mRNA expression and the global DNA methylation level in NSCLC cells carrying KRAS mutation. We further investigated the epigenetic effects of this synergy and found that adding CBD to CIK cells decreased the Long Interspersed Nuclear Element-1 (LINE-1) mRNA expression and the global DNA methylation level in NSCLC cells carrying KRAS mutation. Conclusions: Taken together, CBD holds a great potential for treating NSCLC with CIK cell immunotherapy. In addition, we utilized NSCLC with different driver mutations to investigate the efficacy of CBD. Our findings might provide evidence for CBD-personized treatment with NSCLC patients.

Peptide-drug conjugate designated for targeted delivery to HER2-expressing cancer cells.

Targeted therapy of the highest globally incident breast cancer shall resolve the issue of off-target toxicity concurring with augmented killing of specific diseased cells. Thus, the goal of this study was to prepare a peptide-drug conjugate targeting elevated expression of HER2 receptors in breast cancer. Towards this, the rL-A9 peptide was conjugated with the chemotherapeutic drug doxorubicin (DOX) through a N-succinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC) linker. The synthesized peptide-drug conjugate, rL-A9-DOX, was characterized by mass spectrometry. Molecular docking studies, based on binding energy data, suggested a stronger interaction of rL-A9-DOX with the HER2 receptor in comparison to the unconjugated peptide, rL-A9. The cytotoxic effect of the rL-A9-DOX conjugate was observed to be higher in HER2-positive SKOV3 cells compared to HER2-negative MDA-MB-231 cells, indicating selective cell killing. Cellular internalization of the rL-A9-DOX conjugate was evident from the flow cytometry analysis, where a noticeable shift in mean fluorescent intensity (MFI) was observed for the conjugate compared to the control group. This data was further validated by confocal microscopy, where the fluorescent signal ascertained nuclear accumulation of rL-A9-DOX. The present studies highlight the promising potential of rL-A9-DOX for targeted delivery of the drug into a defined group of cancer cells.

Analysis of the impact of intraventricular hemorrhage on the functional outcome of ruptured anterior cerebral artery aneurysm after clipping.

Background: Various clinical symptoms and variables have been suggested as potential indicators of outcomes in patients with subarachnoid hemorrhage (SAH) resulting from ruptured intracranial aneurysms. The detailed discussion of the consequences of intraventricular hemorrhage (IVH), frequently reported in cases of anterior communicating artery (ACoA) aneurysms, is still pending. The study aimed to assess the results of aneurysm surgery performed early versus delayed in patients with SAH, specifically focusing on the occurrence of IVH. Methods: This study involved patients with ACoA aneurysms who experienced SAH and underwent microsurgical clipping of the aneurysm. A retrospective review was conducted on the patients' medical records. The modified Rankin score was compared between two groups of patients based on the presence or absence of IVH. Results: Ninety-one participants (52 males and 39 females) were included in the study. The initial computed tomography scan showed that 20 patients (with a mean age of 51 ± 13.7 years) had IVH, while 71 patients (with a mean age of 45.8 ± 11.7 years) did not have any signs of IVH. The proportion of patients with poor functional outcomes after six months was 55% in the presence of IVH, compared to 25.4% in patients without IVH, indicating a significant difference in outcome between the two groups (P < 0.016). Conclusion: Patients with SAH having aneurysms located in the ACoA associated with the intraventricular hemorrhage had a poor functional outcome.

'Burn and Push' technique: A novel robotic liver parenchymal transection technique.

BACKGROUND: Liver parenchymal transection during robotic liver resection (RLR) remains a significant challenge due to the limited range of specialised instruments. This study introduces our 'Burn and Push' technique as a novel approach to address these challenges. METHODS: A retrospective analysis was conducted on 20 patients who underwent RLR using the 'Burn and Push' technique at Virginia Commonwealth University Health System from November 2021 to August 2023. The study evaluated peri- and post-operative outcomes. RESULTS: The median operation time was 241.5 min (range, 90-620 min), and the median blood loss was 100 mL (range, 10-600 mL). Major complications occurred in one case, with no instances of postoperative bleeding, bile leak, or liver failure. CONCLUSIONS: The 'Burn and Push' technique is a viable and efficient alternative for liver parenchymal transection in RLR. Further research with larger sample sizes and consideration of the learning curve is necessary to validate these findings.

Robotic management of primary cholecystoduodenal fistula: A case report and brief literature review.

BACKGROUND: Cholecystoduodenal fistula (CDF) arises from persistent biliary tree disorders, causing fusion between the gallbladder and duodenum. Initially, open resection was common until laparoscopic fistula closure gained popularity. However, complexities within the gallbladder fossa yielded inconsistent outcomes. Advanced imaging and robotic surgery now enhance precision and detection. METHOD: A 62-year-old woman with chronic cholangitis attributed to cholecystoduodenal fistula underwent successful robotic cholecystectomy and fistula closure. RESULTS: Postoperatively, the symptoms subsided with no complications during the robotic procedure. Existing studies report favourable outcomes for robotic cholecystectomy and fistula closure. CONCLUSIONS: Our case report showcases a rare instance of successful robotic cholecystectomy with CDF closure. This case, along with a review of previous cases, suggests the potential of robotic surgery as the preferred approach, especially for patients anticipated to face significant laparoscopic morbidity.

Epidemiology of rare bacterial, parasitic, and fungal pathogens in India.

Rare human pathogens are infrequently observed clinically but can lead to undiagnosed infections, delays in treatment, severe complications, including death. Traditional diagnostic tools cannot routinely detect rare infections in public health settings. This study focuses on the incidence and outcomes of rare pathogenic microorganisms over 13 years (2010-2022) using PubMed database to obtain epidemiological data on rare bacterial, parasitic, and fungal infections in hospitals throughout India. A total of 974 articles were screened using case studies, datasets, comments, classical articles, letters, editorials, observational studies, and meta-analyses. Our analysis identified 28 rare bacteria, six parasites, and five fungal species infections in India. Fatal cases were associated with rare bacterial and fungal infections, including two from pan-drug-resistant bacteria (both from the Myroides genus). A total of 10 bacterial species displayed multi-drug resistance; one was extensively drug-resistant, and eight remained unclassified. Of the 83 patients with these rare infections, the mortality was ∼8.4% (seven of 83). Considering drug resistance and high mortality, prompt diagnosis of rare pathogens is crucial to controlling their spread. An increased awareness within the Indian health care system focusing on diagnostics, record keeping, and data sharing will be necessary to enhance surveillance.

Exploring the role of histone deacetylase and histone deacetylase inhibitors in the context of multiple myeloma: mechanisms, therapeutic implications, and future perspectives.

Histone deacetylase inhibitors (HDACis) are a significant category of pharmaceuticals that have developed in the past two decades to treat multiple myeloma. Four drugs in this category have received approval from the U.S. Food and Drug Administration (FDA) for use: Panobinonstat (though canceled by the FDA in 2022), Vorinostat, Belinostat and Romidepsin. The efficacy of this group of drugs is attributed to the disruption of many processes involved in tumor growth through the inhibition of histone deacetylase, and this mode of action leads to significant anti-multiple myeloma (MM) activity. In MM, inhibition of histone deacetylase has many downstream consequences, including suppression of NF-κB signaling and HSP90, upregulation of cell cycle regulators (p21, p53), and downregulation of antiapoptotic proteins including Bcl-2. Furthermore, HDACis have a variety of direct and indirect oxidative effects on cellular DNA. HDAC inhibitors enhance normal immune function, thereby decreasing the proliferation of malignant plasma cells and promoting autophagy. The various biological effects of inhibiting histone deacetylase have a combined or additional impact when used alongside other chemotherapeutic and targeted drugs for multiple myeloma. This helps to decrease resistance to treatment. Combination treatment regimens that include HDACis have become an essential part of the therapy for multiple myeloma. These regimens incorporate drugs from other important classes of anti-myeloma agents, such as immunomodulatory drugs (IMiDs), conventional chemotherapy, monoclonal antibodies, and proteasome inhibitors. This review provides a comprehensive evaluation of the clinical efficacy and safety data pertaining to the currently approved histone deacetylase inhibitors, as well as an explanation of the crucial function of histone deacetylase in multiple myeloma and the characteristics of the different histone deacetylase inhibitors. Moreover, it provides a concise overview of the most recent developments in the use of histone deacetylase inhibitors for treating multiple myeloma, as well as potential future uses in treatment.

Mapping malaria vectors and insecticide resistance in a high-endemic district of Haryana, India: implications for vector control strategies.

BACKGROUND: Achieving effective control and elimination of malaria in endemic regions necessitates a comprehensive understanding of local mosquito species responsible for malaria transmission and their susceptibility to insecticides. METHODS: The study was conducted in the highly malaria prone Ujina Primary Health Center of Nuh (Mewat) district of Haryana state of India. Monthly entomological surveys were carried out for adult mosquito collections via indoor resting collections, light trap collections, and pyrethrum spray collections. Larvae were also collected from different breeding sites prevalent in the region. Insecticide resistance bioassay, vector incrimination, blood meal analysis was done with the collected vector mosquitoes. RESULTS: A total of 34,974 adult Anopheles mosquitoes were caught during the survey period, out of which Anopheles subpictus was predominant (54.7%). Among vectors, Anopheles stephensi was predominant (15.5%) followed by Anopheles culicifacies (10.1%). The Human Blood Index (HBI) in the case of An. culicifacies and An. stephensi was 6.66 and 9.09, respectively. Vector incrimination results revealed Plasmodium vivax positivity rate of 1.6% for An. culicifacies. Both the vector species were found resistant to DDT, malathion and deltamethrin. CONCLUSION: The emergence of insecticide resistance in both vector species, compromises the effectiveness of commonly used public health insecticides. Consequently, the implementation of robust insecticide resistance management strategies becomes imperative. To effectively tackle the malaria transmission, a significant shift in vector control strategies is warranted, with careful consideration and adaptation to address specific challenges encountered in malaria elimination efforts.

Evolving insights into the improvement of adoptive T-cell immunotherapy through PD-1/PD-L1 blockade in the clinical spectrum of lung cancer.

Undeniably, cancer immunotherapies have expanded the spectrum of cancer treatment, however, some patients do not respond to immunotherapies. This scenario is no different for lung cancer, whose two main types, non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), still pose a serious clinical challenge. Adoptive T-cell therapies (ATC), which primarily include cytokine-induced killer (CIK) cell therapy, chimeric antigen receptor T-cell (CAR T-cell) therapy and γδ-T-cell therapy, strengthen the patient's immune system in combating cancer. Combining ATC with immune checkpoint inhibitors (ICI) further enhances the effectiveness of this approach to eradicate cancer. With a particular emphasis on CIK cell therapy, which recently completed 30 years, we highlight the role of the PD-1/PD-L1 axis in NSCLC and SCLC. Besides, we provide insights into the potential synergies of PD-1/PD-L1 inhibitors with adoptive T-cell immunotherapy in reshaping the treatment paradigm for lung cancer.

A dietary commensal microbe enhances antitumor immunity by activating tumor macrophages to sequester iron.

Innate immune cells generate a multifaceted antitumor immune response, including the conservation of essential nutrients such as iron. These cells can be modulated by commensal bacteria; however, identifying and understanding how this occurs is a challenge. Here we show that the food commensal Lactiplantibacillus plantarum IMB19 augments antitumor immunity in syngeneic and xenograft mouse tumor models. Its capsular heteropolysaccharide is the major effector molecule, functioning as a ligand for TLR2. In a two-pronged manner, it skews tumor-associated macrophages to a classically active phenotype, leading to generation of a sustained CD8+ T cell response, and triggers macrophage 'nutritional immunity' to deploy the high-affinity iron transporter lipocalin-2 for capturing and sequestering iron in the tumor microenvironment. This process induces a cycle of tumor cell death, epitope expansion and subsequent tumor clearance. Together these data indicate that food commensals might be identified and developed into 'oncobiotics' for a multi-layered approach to cancer therapy.