The mannose-binding lectin (MBL) gene cloned from Exopalaemon carinicauda plays a key role in resisting infection by Vibrio parahaemolyticus.

Mannose-binding lectin (MBL) is a vital member of the lectin family, crucial for mediating functions within the complement lectin pathway. In this study, following the cloning of the mannose-binding lectin (MBL) gene in the ridgetail white prawn, Exopalaemon carinicauda, we examined its expression patterns across various tissues and its role in combating challenges posed by Vibrio parahaemolyticus. The results revealed that the MBL gene spans 1342 bp, featuring an open reading frame of 972 bp. It encodes a protein comprising 323 amino acids, with a predicted relative molecular weight of 36 kDa and a theoretical isoelectric point of 6.18. The gene exhibited expression across various tissues including the eyestalk, heart, gill, hepatopancreas, stomach, intestine, ventral nerve cord, muscle, and hemolymph, with the highest expression detected in the hepatopancreas. Upon challenge with V. parahaemolyticus, RT-PCR analysis revealed a trend of MBL expression in hepatopancreatic tissues, characterized by an initial increase followed by a subsequent decrease, peaking at 24 h post-infection. Employing RNA interference to disrupt MBL gene expression resulted in a significant increase in mortality rates among individuals challenged with V. parahaemolyticus. Furthermore, we successfully generated the Pet32a-MBL recombinant protein through the construction of a prokaryotic expression vector for conducting in vitro bacterial inhibition assays, which demonstrated the inhibitory effect of the recombinant protein on V. parahaemolyticus, laying a foundation for further exploration into its immune mechanism in response to V. parahaemolyticus challenges.

Prevalence of crimean Congo hemorrhagic fever in Khyber Pakhtunkhwa, Pakistan.

BACKGROUND: CCHFV is well recognized as a major public health threat and its prevalence and epidemiological distribution in Pakistan and specifically in KP province is not well documented. METHODS: We used a gold-standard PCR-based diagnostic assay for confirmation of CCHFV among suspected patients. A total of 150 patients were enrolled from June 2022 to September 2022 and their blood samples were collected for PCR confirmation. RESULTS: The overall positivity rate for CCHFV was 26.67 %, with the virus mostly prevalent in the middle-aged group (21-40 years). In the July of 2022, a significant spike in the prevalence of CCHFV was observed in provincial capital Peshawar with the highest burden (31.57 %). CONCLUSION: Our findings indicate the necessity of strengthening CCHFV monitoring programs and intensifying efforts to identify hotspot regions for effective surveillance and control of CCHFV. The months before the Eid-ul-Adha are crucial in the context of CCHFV control.

De novo transcriptional analysis of the response to starvation stress in the white ridgetail prawn, Exopalaemon carinicauda.

To study the mechanism of the biomolecular response in Exopalaemon carinicauda to starvation stress, we subjected muscle tissue RNA samples from four stress points, including 0 d(control group), 10 d, 20 d, and 30 d, to starvation stress on white ridgetail prawn with a body weight of 1.41 + 0.42 g, aquaculture water temperature of 23-25 °C, salinity of 26, dissolved oxygen ≥5 mg/L, and pH 8-8.5, Then performed de novo transcriptome assembly and gene expression analysis using BGISEQ-500 with a tag-based digital gene expression (DGE) system. By de novo assembling at the four times, we obtained 28,167, 21,115, 24,497, and 27,080 reads, respectively. The results showed that the stress at 10 d led to no significant difference in the expressed genes, while the stress at 20 d and 30 d showed a significant increase (or decrease) in the expression of 97 (276) and 143 (410) genes, respectively, which were involved in 8 different metabolic pathways. In addition, we detected 2647 unigene transcription factors. Eleven upregulated and sixteen downregulated genes from the different starvation stress groups were choose to verify the reliability of the transcriptome data, and the results showed that the expression trends of these genes were consistent with the results shown by the transcriptome. The analysis of the experimental data and our discussion of the response mechanism of white ridgetail prawn under starvation stress provides a foundation for further screening of the key genes of starvation stress and may help to elucidate their functions.

An Extremely Rare Case of Prostate and Bladder Wall Involvement of Chronic Lymphocytic Leukemia.

Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults and is characterized by monoclonal proliferation of B-cell lymphocytes which are morphologically mature, but immunologically dysfunctional. The primary sites of disease involvement include peripheral blood, lymph nodes, spleen, and bone marrow. CLL can also present locally and aggressively at extranodal sites. We describe the case of a 74-year-old gentleman with multiple medical comorbidities who was Foley catheter-dependent at baseline for bladder outlet obstruction. He was detected to have Rai stage I CLL following an inguinal lymph node biopsy and was on regular outpatient surveillance. Later, he underwent a prostate biopsy for evaluation of hematuria, results of which were consistent with CLL involvement in the prostate and urinary bladder. The patient was started on single-agent ibrutinib, and demonstrated an excellent clinical response to bladder outlet obstruction. His long-term Foley catheter was discontinued within 5 days of ibrutinib therapy. Unfortunately, 1 year later, he had disease progression, and therapy was changed to a single-agent rituximab, to which he is responding well. Our case is unique as it brings up the first reported case of prostate and bladder wall CLL.

Efficacy and Safety of Brivaracetam in Persons With Epilepsy in a Real-World Setting: A Prospective, Non-Interventional Study.

BACKGROUND AND AIM: Epilepsy stands out as one of the most prevalent neurological conditions. Brivaracetam (BRV) is a noteworthy antiseizure medication (ASM) distinguished by its pronounced and selective interaction with the synaptic vesicle protein 2A (SV2A) within the brain. Prior investigations, including regulatory trials, post-marketing assessments, and comparative meta-analyses, have consistently underscored BRV's equivalency in efficacy and superior tolerability when pitted against other antiseizure drugs. This study aimed to evaluate the effectiveness, safety, and acceptability of BRV in treating epileptic patients in the Pakistani population. METHODS: This prospective observational study, conducted in Pakistan from February to December 2022, employed a non-probability consecutive sampling technique. This study included 368 adult patients diagnosed with epilepsy, with a focus on those aged 18 and above experiencing focal seizures. Demographic data, clinical history, seizure types, and epilepsy profiles were recorded. Patients were administered BRV (Brivera; manufactured by Helix Pharma Pvt Ltd., Sindh, Pakistan) monotherapy therapy under physician guidance and followed up for three months. The study assessed changes in seizure frequency, side effects, and drug resistance at baseline, 14th day, and 90th day. Safety aspects were monitored, including documenting any adverse effects associated with BRV therapy. RESULTS: A total of 368 epileptic patients were included in this study, of which 287 (61.3%) were males and 181 (38.7%) were females. The mean age was 32.91±17.11 years. The mean number of seizures at the baseline visit was 5.74±6.21, at 14 days was 2.89±3.84 and at 90 days was 1.73±5.01 (p<0.001). Overall, a more than 50% reduction in seizure episodes was achieved in 178 (56.3%) patients at day 90, and less than 50% reduction in seizure episodes was achieved by 95 (26.8%) patients on Day 14, with a highly significant association between them (p<0.001). Among 316 patients, only 41 (4.4%) of all BRV-treated patients experienced adverse events; Of these 41 patients, 17 (41.7%) reported dizziness and 14(34.2%) reported behavioral issues. CONCLUSIONS: Epileptic patients receiving BRV demonstrated a substantial reduction of greater than 50% seizure episodes at the end of follow-up visits. Moreover, BRV exhibited fewer adverse effects in individuals with epilepsy.

Pembrolizumab-Induced Acute Skin Reaction: A Case Report and Review of Literature.

The development of immune checkpoint inhibitors is considered to be one of the most important advances in cancer treatment. Pembrolizumab is an immune checkpoint inhibitor against programmed death-ligand 1 (PD-L1) receptor that has demonstrated antineoplastic activity against various malignancies including non-small cell lung cancer, melanoma, and triple-negative breast cancer. Pembrolizumab has been associated with significant dermatological adverse reactions, referred to as immune-related adverse events. The cutaneous adverse effects can affect the quality of life of the patient and can result in dose reduction or even discontinuation of the treatment. Hence it is of utmost importance to have a comprehensive understanding of the cutaneous toxicities for prompt initiation of treatment. We present the case of a 49-year-old male with metastatic non-small cell lung cancer (NSCLC) with 100% PD-L1 expression, who suffered a severe cutaneous reaction involving more than 95% of body surface area, following the first dose of pembrolizumab. He was treated with low-dose systemic steroids (prednisone 10 mg), to which he responded well. Since the patient showed excellent symptomatic and clinical response to pembrolizumab, it was not discontinued. The patient has not developed a rash with subsequent doses of pembrolizumab, and the steroids were tapered off.

Resolution of Chronic Immune Thrombocytopenia Purpura after Autologous Hematopoietic Stem Cell Transplantation for Diffuse Large B-Cell Lymphoma.

Immune thrombocytopenic purpura (ITP) is a hematological disorder characterized by immune-mediated destruction of platelets that could be triggered by a number of causes. ITPs are usually treated with steroid, immunomodulators or immunosuppressors, and intravenous immunoglobulin therapy though refractory/relapsed status frequently occurs. It was suggested that autologous hematopoietic stem cell transplant (HSCT) after high-dose chemotherapy conditioning might improve ITP patients' peripheral blood platelet counts via reorganizing disrupted immune balance in the hematopoietic and hematologic systems. In this case report, we describe how a patient, who suffered from both severe thrombocytopenia due to chronic ITP and refractory/relapsed diffuse large B-cell lymphoma (DLBCL), was managed to successfully receive autologous HSCT using carmustine, etoposide, cytarabine and melphalan (BEAM) conditioning regimens and how his chronic ITP was eventually cured after receiving autologous HSCT. This is the first clinical case in the world demonstrating that high-dose BEAM chemotherapy conditioned autologous HSCT could cure chronic ITP while successfully managing refractory/relapse DLBCL. The clinical hematology professionals and the patients will benefit from our experience in managing severe thrombocytopenia while conducting high-dose chemotherapy conditioning and autologous HSCT for DLBCL.

Mucosal Melanoma: A Rare Entity and Review of the Literature.

Mucosal melanoma is a rare variant of melanoma representing around 1% of total cases of melanoma diagnosed. The usual sites of mucosal involvement are the sino-nasal passages, the oral cavity, and less commonly the upper gastrointestinal (GI) tract. It also has been reported to occur in vulvovaginal and anorectal mucosa.  We present a rare case of mucosal melanoma that presented as recurrent epistaxis, headache, and sinus pressure. CT maxillofacial imaging revealed a large mass right nasal cavity. This was biopsied by ENT and shown to be mucosal melanoma. This was treated with palliative radiation followed by immunotherapy with nivolumab.  Along with details of the case, we also discuss current treatment options with a focus on the role of immunotherapy and its efficacy in cases of head and neck mucosal melanoma. Our review of literature supports use of combination immunotherapy (including both nivolumab and ipilimumab) as it shows greater efficacy than either therapy alone. When combined with radiation therapy (RT) the overall response rate is improved and RT induces an abscopal effect; where benefits of RT are also seen at nonirradiated locations.  In our patient, the use of radiation was essentially palliative as the patient was deemed to not be a surgical candidate. We discuss in our literature review the optimum timing of radiation in relation to definitive surgery or immunotherapy.

Clinical Profile and Prognosis of Cerebral Venous Sinus Thrombosis.

Introduction Cerebral venous sinus thrombosis (CVST) is an acute cerebrovascular disease diagnosed nowadays more frequently. Magnetic resonance venogram (MRV) is the modality of choice for accurate diagnosis. Young females in their childbearing age are prone to develop CVST. Clinical presentation is mainly with headache, focal neurologic deficits, and seizures. Around one third of the patients have altered sensorium at presentation. Prognosis of CVST is good if diagnosed and treated early. Long-term deficits may remain in one quarter of patients. The aim of our study was to do clinical profiling and prognosis of CVST patients. Materials and methods This is a descriptive study conducted at the department of Neurology, Sheikh Zayed Medical College/Hospital, Rahim Yar Khan. Study duration was one year. Patients fulfilling inclusion and exclusion criteria were included in the study. Patients confirmed to have CVST on magnetic resonance imaging (MRI)/MRV were included in final analysis. Ethical approval was taken from the Institutional Review Board.  Results Thirty three out of 54 patients were included in the final analysis. Out of them, 29 (87.8%) were females and four (12.1%) were males. The mean age at the time of presentation was 31.36 ± 9.61. Of the 29 females, only three were pregnant and 26 were in the postpartum period at the time of presentation. Twelve (41.4%) females were primigravida. Focal deficits were present in 30 (90.9%) patients; headache was present in 26 (78.8%) patients; seizures were present in 24 (72.7%) patients on presentation; and anemia was present in 20 (60.6%) patients. Conclusion CVST is an important cause of intracranial hypertension, seizures, and stroke in young people. Clinical presentation is extremely variable, and a high index of suspicion is needed. Magnetic resonance imaging brain with MRV is the current diagnostic modality of choice. Medical management with anticoagulants and supportive measures has excellent clinical outcomes.

Treatment and survival rates of stage IV pancreatic cancer at VA hospitals: a nation-wide study.

BACKGROUND: Metastatic pancreatic cancer (MPC) is associated with an extremely high mortality. Current NCCN guidelines recommend systemic therapy, as it is superior to best supportive care. Undertreatment of MPC continues to be an issue. Recent treatment and survival data of MPC in Veterans' Affairs' (VA) hospitals have not been published. The relationship between MPC treatment and survival and the American College of Surgeons' (ACS) Committee on Cancer (CoC) accreditation in VA hospitals has not been studied. METHODS: Nationwide data from the National Veterans Affairs Cancer Cube Registry was analyzed. In total, 6,775 patients were diagnosed with MPC between 2000 and 2014. CoC accreditation of each VA hospital was obtained using the ACS website. RESULTS: MPC constitutes 52.31% of all pancreatic cancer diagnosed (6,775/12,951 cases). The near totality was men (97.44%). The above 70 years age group and the 60-70 years age group were the most common ages at diagnosis with 39.39% and 38.02% respectively. The proportion of early-onset pancreatic cancer (EOPC) was 2.84%. When compared to all stages of pancreatic cancer, stage IV pancreatic cancer had a lower proportion of cancer originating from the head of the pancreas (39.33% versus 50.63%) and more originating from the tail (17.99% versus 13.39%). Tumors originating from head of the pancreas are more likely to cause biliary symptoms and thus are more likely to be caught at an earlier stage. Overall, treatment rate in the VA at the national level with first-line chemotherapy was 37.61%. The rate of treatment over the years has increased in a linear fashion from 33.01% in 2000 to 41.95% in 2014. This has corresponded with an increase of 1-5 years survival of 9.29% in 2000 to 22.99% in 2014 and 5-10 years survival from 0.96% in 2000 to 6.00% in 2012. Treatment rates in CoC-accredited and non-CoC accredited VA hospitals were similar (38.94% and 38.12%, respectively). Survival rates in CoC-accredited and non-COC accredited VAs were similar with a 1-5 years survival rate of 8.89% and 8.57%, respectively. CONCLUSIONS: Treatment and survival of MPC have risen significantly in the past decade at VA hospitals. CoC accreditation is not associated with a change in treatment or survival rates.

Optimizing adjuvant endocrine therapy for early ER+ breast cancer: An update for surgeons.

INTRODUCTION: The optimal duration of adjuvant endocrine therapy in early ER + breast cancer has been controversial. This article aims to provide an overview of the evidence. METHODS: A search of the literature was conducted via MEDLINE using appropriate keywords. Eligible studies were screened and relevant articles were selected for this report. RESULTS: Studies investigating the role of extended adjuvant tamoxifen beyond 5 years have revealed mixed results depending on the proportion of node positivity. In postmenopausal women, aromatase inhibitors (AIs) for 5 years are superior to tamoxifen. Extending the use of AIs beyond 5 years seem to reduce the risk of relapse in postmenopausal women with node positive disease. The addition of bisphosphonates to counteract AI-related osteopenia may further improve overall and disease-free survival. Women younger than 40 years seem to benefit from ovarian suppression combined with tamoxifen or exemestane. CONCLUSIONS: An individualised approach is required for every patient. The adverse effects of endocrine therapy should be weighed against the potential benefits of extended therapy to better inform decision-making.

The Impact of EndoPredict Clinical Score on Chemotherapy Recommendations in Women with Invasive ER+/HER2- Breast Cancer Stratified as Having Moderate or Poor Prognosis by Nottingham Prognostic Index.

BACKGROUND: The Nottingham Prognostic Index (NPI) was developed using tumour pathological features to guide decisions regarding adjuvant therapy in breast cancer. Recent breakthroughs in molecular biology aided development of genomic assays such as EndoPredict, which have been shown to provide excellent prognostic information. The current study investigated the impact of EndoPredict Clinical (EPClin), a composite of clinicopathological data and EndoPredict score, on chemotherapy recommendations based on NPI. PATIENTS AND METHODS: A total of 120 patients with oestrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer who were candidates for post-operative adjuvant chemotherapy at a single tertiary centre were included. Both NPI and EPClin were applied to all patients. NPI differentiated patients into groups with excellent/good prognosis (N=41; NPI≤3.4) or moderate/poor prognosis (N=79; NPI >3.4). The latter were considered for adjuvant chemotherapy. RESULTS: There was discordance in results of 31% of cases; 35% of the patients/candidates for adjuvant chemotherapy according to NPI were reclassified as being at low risk of recurrence by EPClin. CONCLUSION: Genomic profiling using EPClin reduces the potential need for adjuvant chemotherapy in women with ER+/HER2- breast cancer who are candidates for chemotherapy according to the NPI.

Sunitinib-Induced Acute Interstitial Nephritis in a Thrombocytopenic Renal Cell Cancer Patient.

Sunitinib, a multitargeted tyrosine kinase inhibitor (TKI), is currently the standard of care for patients with metastatic renal cell carcinoma. Renal adverse events associated with sunitinib include proteinuria, renal insufficiency secondary to focal segmental glomerulosclerosis (FSGS), and thrombotic microangiopathy. We describe the second reported instance of biopsy-proven sunitinib-induced acute interstitial nephritis (AIN), in a challenging case complicated by thrombocytopenia. The case illustrates the importance of early diagnosis and intervention in ensuring long-term recovery from renal complications. Four other cases of AIN reported along with inhibition of the vascular endothelial growth factor (VEGF) by either TKI (sunitinib and sorafenib) or antibodies (bevacizumab) suggest a possible class effect. Given our experience, we recommend monitoring renal function with VEGF inhibition, and in the case of renal failure in the setting of an unclear diagnosis, we recommend prompt biopsy.

Pleomorphic lobular carcinoma in situ: Current evidence and a systemic review.

Pleomorphic lobular carcinoma in situ (PLCIS) has only recently been identified as a distinct pathological entity within classic lobular carcinoma in situ (CLCIS). As such, there is currently no consensus among clinicians regarding the optimal treatment of this disease. The present study determined the risk of concomitant invasive disease and ductal carcinoma in situ (DCIS) if PLCIS is observed on core needle biopsy (CNB) and collated the evidence regarding the risk of recurrence in relation to surgical margins and adjuvant therapy. In addition, the pertinent literature available through MedLine, PubMed, the WHO Clinical Trials Registry Platform and Google Scholar using appropriate keywords was reviewed. The pooled results of studies in the literature demonstrated a concomitant presence of invasive disease of 40%, and 15% for DCIS. The studies that examined recurrence rates indicated that the risk is reduced with ample resection margins (>2 mm) and adjuvant radiotherapy. However, recent studies raise concerns regarding breast conservation when pursuing clear margins. No level 1 evidence from prospective studies, randomized controlled trials (RCTs), or meta-analyses based on such RCTs was identified. This is a clinical issue that warrants investigation in appropriately powered well designed prospective studies for a satisfactory resolution of all concerns.

Effect of the knockdown of death-associated protein 1 expression on cell adhesion, growth and migration in breast cancer cells.

Death-associated protein 1 (DAP1) is a highly conserved phosphoprotein involved in the regulation of autophagy. A previous clinical study by our group suggested an association between low DAP1 expression and clinicopathological parameters of human breast cancer. In the present study, we aimed to determine the role of DAP1 in cancer cell behaviour in the context of human breast cancer. We developed knockdown sublines of MCF7 and MDA-MB­231, and performed growth, adhesion and invasion assays and electric cell-substrate impedance sensing (ECIS) studies of the post-wound migration of cells. In addition, we studied the mRNA expression of caspase 8 and 9, DELE, IPS1, cyclin D1 and p21 in the control and knockdown sublines. Knockdown was associated with increased adhesion and migration, significantly so in the MDA-MB-231DAP1kd cell subline (p=0.029 and p=0.001, respectively). Growth in MCF7 cells showed a significant suppression on day 3 (p=0.029), followed by an increase in growth matching the controls on day 5. While no change in the apoptotic response to serum starvation could be attributed to DAP1 knockdown, the expression of known components of the apoptosis pathway (caspase 8) and cell cycle (p21) was significantly reduced in the MCF7DAP1kd cell subline (p≤0.05), while in MDA-MB-231DAP1kd the expression of a pro-apoptotic molecule, IPS1, was suppressed (p≤0.05). DAP1 may have an important role in cell adhesion, migration and growth in the context of breast cancer and has significant associations with the apoptosis pathway. Furthermore, we believe that delayed increase in growth observed in the MCF7DAP1kd cell subline may indicate activation of a strongly pro-oncogenic pathway downstream of DAP1.

Current state of mTOR targeting in human breast cancer.

BACKGROUND/AIM: The mammalian, or mechanistic, target of rapamycin (mTOR) pathway has been implicated in several models of human oncogenesis. Research in the role of mTOR in human oncogenesis remains a field of intense activity. In this mini-review, we intend to recount our current understanding of the mTOR pathway, its interactions, and its role in human carcinogenesis in general, and breast cancer in particular. MATERIALS AND METHODS: We herein outline the discrete components of the two complexes of mTOR, and attempt to define their distinct roles and interactions. Furthermore, we review current developments in the therapeutic targeting of mTOR in human breast cancer. RESULTS: Our understanding of the organisation and interactions of the mTOR pathway continues to evolve. There has been significant incremental, albeit slow, progress in the therapeutic targeting of the mTOR pathway in human breast cancer. CONCLUSION: Continued progress in the field would require a better understanding of the role of the mTOR pathway in human breast cancer. By summarizing the current literature, this review will provide useful information on the topic.

Morphology of the proximal femur in a Pakistani population.

PURPOSE: To measure the morphology of the proximal femur in a Pakistani population. METHODS: Standardised anteroposterior pelvic radiographs of 116 male and 20 female healthy volunteers aged 20 to 50 (mean, 33) years were taken. Morphologic dimensions of the proximal femur were measured, including canal flare index (CFI), morphological cortical index (MCI), femoral head offset, femoral head diameter, and femoral head position. RESULTS: Based on the CFI, 67% of the subjects had normal canal shapes (CFI, 3.0-4.7), whereas 1% and 33% of the subjects had stovepipe shapes (CFI, <3) and champagne-flute shapes (CFI, 4.7-6.5), respectively. Based on the MCI, 29% of the subjects had cylindrical shapes (MCI, <2.7) and 71% had trumpet shapes (MCI, >2.7). CONCLUSION: Morphology of the proximal femur in our study population differed significantly from those in western populations, indicating regional variation. It could also be due to the younger age of our population.